5-Amino-Oxazepine and 5-Amino-Thiazepane Compounds as Beta Secretase Antagonists and Methods of Use

ABSTRACT

The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula (I); wherein variables A 1 , A 3 , A 4 , A 5 , A 6 , A 8 , R 2 , R 7 , X and Y of Formula (I) are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and corresponding uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer&#39;s Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formulas (II) and sub-formula embodiments of Formula (I) and (II), intermediates and processes and methods useful for the preparation of compounds of Formulas (I)-(II).

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/440,270, filed on Feb. 7, 2011, which specificationis hereby incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The invention relates generally to pharmaceutically active compounds,pharmaceutical compositions and methods of use thereof, to treatbeta-secretase mediated diseases and conditions, including, withoutlimitation, Alzheimer's disease, plaque formation and related centralnervous system (CNS) disorders.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) affects greater than 12 million aging peopleworldwide, and importantly, the number affected continues to grow. ADaccounts for the majority of dementia clinically diagnosed after the ageof 60. AD is generally characterized by the progressive decline ofmemory, reasoning, judgement and orientation. As the disease progresses,motor, sensory, and vocal abilities are affected until there is globalimpairment of multiple cognitive functions. The loss of cognitivefunction occurs gradually, typically leading to a diminished cognitionof self, family and friends. Patients with severe cognitive impairmentand/or diagnosed as end-stage AD are generally bedridden, incontinent,and dependent on custodial care. The AD patient eventually dies in aboutnine to ten years, on average, after initial diagnosis. Due to theincapacitating, generally humiliating and ultimately fatal effects ofAD, there is a need to effectively treat AD upon diagnosis.

AD is characterized by two major physiological changes in the brain. Thefirst change, beta amyloid plaque formation, supports the “amyloidcascade hypothesis” which conveys the thought that AD is caused by theformation of characteristic beta amyloid peptide (A-beta), or A-betafragments thereof, deposits in the brain (commonly referred to as betaamyloid “plaques” or “plaque deposits”) and in cerebral blood vessels(beta amyloid angiopathy). A wealth of evidence suggests thatbeta-amyloid and accompanying amyloid plaque formation is central to thepathophysiology of AD and is likely to play an early role in thisintractable neurodegenerative disorder. The second change in AD is theformation of intraneuronal tangles, consisting of an aggregate form ofthe protein tau. Besides being found in patients with AD, intraneuronaltangles are also found in other dementia-inducing disorders. Joachim etal., Alz. Dis. Assoc. Dis., 6:7-34 (1992).

Several lines of evidence indicate that progressive cerebral depositionof A-beta plays a seminal role in the pathogenisis of AD and can precedecognitive symptoms by years or even decades. Selkoe, Neuron, 6:487(1991). Release of A-beta from neuronal cells grown in culture and thepresence of A-beta in cerebrospinal fluid (CSF) of both normalindividuals and AD patients has been demonstrated. Seubert et al.,Nature, 359:325-327 (1992). Autopsies of AD patients have revealed largenumbers of lesions comprising these 2 factors in areas of the humanbrain believed to be important for memory and cognition.

Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloid containing plaques and vascular amyloid angiopathywere also found in the brains of individuals with Down's Syndrome,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type(HCHWA-D), and other neurodegenerative disorders.

It has been hypothesized that A-beta formation is a causative precursoror factor in the development of AD. More specifically, deposition ofA-beta in areas of the brain responsible for cognitive factors isbelieved to be a major factor in the development of AD. Beta amyloidplaques are primarily composed of amyloid beta peptide (A-beta peptide).A-beta peptide is derived from the proteolytic cleavage of a largetransmembrane amyloid precursor protein (APP), and is a peptide rangingin about 39-42 amino acid residues. A-beta 42 (42 amino acids long) isthought to be the major component of these plaque deposits in the brainsof Alzheimer's Disease patients. Citron, Trends in PharmacologicalSciences, 25(2):92-97 (2004).

Similar plaques appear in some variants of Lewy body dementia and ininclusion body myositis, a muscle disease. Aβ also forms aggregatescoating cerebral blood vessels in cerebral amyloid angiopathy. Theseplaques are composed of a tangle of regularly ordered fibrillaraggregates called amyloid fibers, a protein fold shared by otherpeptides such as prions associated with protein misfolding diseases.Research on laboratory rats suggest that the two-molecule, soluble formof the peptide is a causative agent in the development of Alzheimer'sand that the two-molecule form is the smallest synaptotoxic species ofsoluble amyloid beta oligomer. Shankar, G. M., Nature Medicine (Jun. 22,2008) online doi 10:1038 nm 1782.

Several aspartyl proteases, including beta-secretase andgamma-secretase, are thought to be involved in the processing orcleavage of APP, resulting in the formation of A-beta peptide. Betasecretase (BACE, also commonly referred to as memapsin) is thought tofirst cleave APP to generate two fragments: (1) a first N-terminusfragment (beta APP) and (2) a second C-99 fragment, which issubsequently cleaved by gamma secretase to generate the A-beta peptide.APP has also found to be cleaved by alpha-secretase to producealpha-sAPP, a secreted form of APP that does not result in beta-amyloidplaque formation. This alternate pathway precludes the formation ofA-beta peptide. A description of the proteolytic processing fragments ofAPP is found, for example, in U.S. Pat. Nos. 5,441,870, 5,712,130 and5,942,400.

BACE is an aspartyl protease enzyme comprising 501 amino acids andresponsible for processing APP at the beta-secretase specific cleavagesite. BACE is present in two forms, BACE 1 and BACE 2, designated assuch depending upon the specific cleavage site of APP. Beta secretase isdescribed in Sinha et al., Nature, 402:537-554 (1999) (p 510) and PCTapplication WO 2000/17369. It has been proposed that A-beta peptideaccumulates as a result of APP processing by BACE. Moreover, in vivoprocessing of APP at the beta secretase cleavage site is thought to be arate-limiting step in A-beta production. Sabbagh, M. et al., Alz. Dis.Rev. 3:1-19 (1997). Thus, inhibition of the BACE enzyme activity isdesirable for the treatment of AD.

Studies have shown that the inhibition of BACE may be linked to thetreatment of AD. The BACE enzyme is essential for the generation ofbeta-amyloid or A-beta. BACE knockout mice do not produce beta-amyloidand are free from Alzheimer's associated pathologies including neuronalloss and certain memory deficits. Cole, S. L., Vasser, R., MolecularDegeneration 2:22, 2007. When crossed with transgenic mice that overexpress APP, the progeny of BACE deficient mice show reduced amounts ofA-beta in brain extracts as compares with control animals (Luo et al.,Nature Neuroscience, 4:231-232 (2001)). The fact that BACE initiates theformation of beta-amyloid, and the observation that BACE levels areelevated in this disease provide direct and compelling reasons todevelop therapies directed at BACE inhibition thus reducing beta-amyloidand its associated toxicities. To this end, inhibition of beta secretaseactivity and a corresponding reduction of A-beta in the brain shouldprovide a therapeutic method for treating AD and other beta amyloid orplaque related disorders.

Consequently, the approach of regulating or reducing the formation ofA-beta peptide formation and deposition as a potential treatment for ADhas received tremendous attention and belief from both researchers andinvestors alike. A small molecule gamma-secretase inhibitor, LY450139(“Semagacestat”), an A-beta lowering agent, is in phase II and Phase IIIclinical trials for the treatment of Alzheimer's Disease. Thepharmacokinetics of semagacestat in plasma, as well as the plasma andcerebral spinal fluid (CSF) A-Beta peptide levels as pharmacodynamicresponses to semagacestat administration were evaluated in healthy humansubjects in single and multiple doses, and pharmacokinetic andpharmacodynamic changes were also assessed in mild to moderate ADpatients in two (2) clinical trials (Expert Opin. Pharmacother. (2009),10 (10); Clin. Neuropharmacol. 2007; 30 (pgs 317-325); and Neurology,2006, 66 (pgs 602-624)).

Additional approaches have been taken in attempts to treat AD andplaque-related disorders. One such approach to reduce the formation ofplaque on the brain involves the inhibition of and, therefore, thereduction of BACE activity. For example, each of the following PCTpublications: WO 07/058602, WO 10/021680, WO 10/105179, WO 06/041404, WO07/114771, WO 08/076045, WO 08/076046, WO 08/150217, WO 07/038271, WO09/091016, WO 08/108378, WO 09/134617, WO 05/097767, WO 08/092785, WO06/138265, WO 08/103351, WO 06/138230, WO 08/200445, WO 06/111370, WO07/287692, WO 05/058311, EP 01942105, WO 08/133273, WO 08/133274, WO07/049532, US20070027199, WO 07/038271, US20070072925, US20070203116,US20050282826, WO 08/118379, WO 06/076284, US20070004786, WO 06/083760,WO 07/011810, WO 07/011833, WO 08/054698 and WO10/128058, describeinhibitors of BACE, useful for treating AD and other beta-secretasemediated disorders.

Despite the many efforts and resources directed to researching A-betalowering agents, there remains a need to identify safe and efficacioustreatment agents for AD.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful for themodulation of beta secretase activity, and as treatment of AD.Particularly, the compounds of the invention are useful for theregulation or reduction of the formation of A-beta peptide and,consequently, the regulation and/or reduction of formation of betaamyloid plaque both on the brain, as well as in the CNS. To this end,the compounds are useful for the treatment of AD and other betasecretase and/or plaque-related and/or mediated disorders. For example,the compounds are useful for the prophylaxis and/or treatment, acuteand/or chronic, of AD and other diseases or conditions involving thedeposition or accumulation of beta amyloid peptide, and formation ofplaque, on the brain.

The compounds provided by the invention, including stereoisomers,tautomers, hydrates, solvates and pharmaceutically acceptable saltsthereof, are generally defined by Formula I

wherein each of A¹, A³, A⁴, A⁵, A⁶, R², R⁷, X and Y of Formula I aredefined below. The invention also provides procedures for makingcompounds of Formula, and sub-Formulas thereof, as well as intermediatesuseful in such procedures.

The invention further provides pharmaceutical compositions comprisingcompounds of the invention, methods for the treatment of beta secretasemediated diseases using both the compounds and compositions of theinvention. For example, and in one embodiment, the invention provides apharmaceutical composition comprising an effective dosage amount of acompound of Formula I in association with at least one pharmaceuticallyacceptable excipient.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, there are provided compounds,including stereoisomers, tautomers, hydrates, solvates andpharmaceutically acceptable salts thereof, which are generally definedby Formula I:

wherein

A¹ is CR¹ or N;

A³ is CR³ or N;

A⁴ is CR⁴ or N;

A⁵ is CR⁵ or N;

A⁶ is CR⁶ or N;

A⁸ is CR⁸ or N, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶ andA⁸ is N;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or —Si(CH₃)₃, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NHC(═O)R⁹, —C(═O)NHR⁹,—NHS(O)₂R⁹, —S(O)₂NHR⁹, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹;

each R⁹, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, morpholinyl, pyrazolyl, isoxazolyl,dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,oxetanyl or dioxolyl, wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkylamino-, C₁₋₆dialkylamino-,C₁₋₆alkoxyl, C₁₋₆thioalkoxyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, morpholinyl, pyrazolyl,isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, isoptionally substituted independently with 1-5 substituents of F, Cl, CN,NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,C₁₋₃alkylamino-, C₁₋₃dialkylamino, C₁₋₃thioalkoxyl, or oxetanyl; and

—X—Y— taken together is —CR¹⁰R¹⁰—O—, —O—CR¹⁰R¹⁰—, —CR¹⁰R¹⁰—S— or—S—CR¹⁰R¹⁰, wherein each R¹⁰, independently, is H or F.

In another embodiment of the present invention, the compounds, andsolvates, tautomers, hydrates, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula I, wherein

A¹ is CH or CF;

A³ is CH, CF or N;

A⁴ is CH, CF or N;

A⁵ is CH;

A⁶ is CH;

A⁸ is CH;

R² is C₃₋₆-alkyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, phenyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyranyl,tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl or8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, wherein the C₃₋₆-alkyl, C₂₋₄alkynyl,—OC₁₋₆alkyl, —SC₁₋₆alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, dihydropyranyl, tetrahydropyranyl, pyrrolidinyl,piperidinyl, morpholinyl and 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, areoptionally substituted, independently, with 1-5 substituents of R⁹;

R⁷ is C₂₋₄alkynyl, —OC₁₋₆alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl orpyridazinyl, wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, pyrimidyl,pyrazinyl and pyridazinyl are optionally substituted, independently,with 1-3 substituents of R⁹;

each R⁹, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl; and

—X—Y— taken together is —CR¹⁰R¹⁰—O—, —O—CR¹⁰R¹⁰—, —CR¹⁰R¹⁰—S— or—S—CR¹⁰R¹⁰, wherein each R¹⁰, independently, is H or F.

In another embodiment of the present invention, the compounds, andhydrates, solvates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula II

wherein

A³ is CR³ or N;

A⁴ is CR⁴ or N, provided that no more than one of A³ and A⁴ is N;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or —Si(CH₃)₃, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NHC(═O)R⁹, —C(═O)NHR⁹,—NHS(O)₂R⁹, —S(O)₂NHR⁹, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹;

each R⁹, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, morpholinyl, pyrazolyl, isoxazolyl,dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,oxetanyl or dioxolyl, wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkylamino-, C₁₋₆dialkylamino-,C₁₋₆alkoxyl, C₁₋₆thioalkoxyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, morpholinyl, pyrazolyl,isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, isoptionally substituted independently with 1-5 substituents of F, Cl, CN,NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,C₁₋₃alkylamino-, C₁₋₃dialkylamino, C₁₋₃thioalkoxyl, or oxetanyl; and

—X—Y— taken together is —CR¹⁰R¹⁰—O—, —O—CR¹⁰R¹⁰—, —CR¹⁰R¹⁰—S— or—S—CR¹⁰R¹⁰, wherein each R¹⁰, independently, is H or F.

In another embodiment of the present invention, the compounds, andsolvates, tautomers, stereoisomers and pharmaceutically acceptable saltsthereof, are defined by Formula II-A

wherein each of R², R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ is as defined above withrespect to Formula I or Formula II.

In another embodiment of the present invention, the compounds, andhydrates, solvates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula III

wherein

A³ is CR³ or N;

A⁴ is CR⁴ or N, provided that no more than one of A³ and A⁴ is N;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or —Si(CH₃)₃, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl or cyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl,pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R⁹;

each R⁹, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperazinyl, oxetanyl or dioxolyl,wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl,oxetanyl or dioxolyl, is optionally substituted independently with 1-5substituents of F, Cl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl,ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, C₁₋₃alkylamino-, C₁₋₃dialkylamino,C₁₋₃thioalkoxyl, or oxetanyl; and

—X— is —CR¹⁰R¹⁰, wherein each R¹⁰, independently, is H or F.

In another embodiment of the present invention, the compounds, andhydrates, solvates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula IV

wherein

A³ is CR³ or N;

A⁴ is CR⁴ or N, provided that no more than one of A³ and A⁴ is N;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃,C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or —Si(CH₃)₃, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl,—N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl;

R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl or cyclohexyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl,pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-5 substituents of R⁹;

each R⁹, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkoxyl, C₁₋₆thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl,dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,oxetanyl or dioxolyl, wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkylamino-, C₁₋₆alkoxyl,C₁₋₆thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,pyrrolidinyl, oxetanyl or dioxolyl, is optionally substitutedindependently with 1-5 substituents of F, Cl, CN, NO₂, NH₂, OH, oxo,methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl,isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,C₁₋₃alkylamino-, C₁₋₃thioalkoxyl, or oxetanyl; and

—Y— is —CR¹⁰R¹⁰, wherein each R¹⁰, independently, is H or F.

The present invention contemplates that the various differentembodiments of Formulas I, II, III and IV, and sub-Formulas thereof,described herein, may comprise the following embodiments with respect toindividual variables of A¹, A³, A⁴, A⁵, A⁶, A⁸, R², R⁷, X and Y whereapplicable, as described below. Hence, these embodiments with respect toindividual variables A¹, A³, A⁴, A⁵, A⁶, A⁸, R², R⁷, X and Y, whereapplicable, may be applied “in conjunction with any of the other {aboveand below} embodiments” to create various embodiments of generalFormulas I, II, III and IV and each sub-formula thereof, which are notliterally described herein.

In another embodiment, the invention includes compounds wherein A¹ isCH, CF or N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ is CHor CF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A³ isCH, CF or N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A³ is CHor N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A³ is CHor CF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A³ isCF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A³ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ isCH, CF or N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ is CHor CF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ is CFor N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ is CHor N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ isCF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁴ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁵ isCH, CF or N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁵ is CHor CF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁵ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁶ isCR⁶ wherein R⁶ is H, F, Br or

or A⁶ is N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁶ isCH, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁶ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁸ isCR⁸ wherein R⁸ is F, Br or

in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁸ isCH, CF or N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁸ is CHor CF, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A⁸ is N,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹ or N, A³ is CR³ or N, A⁴ is CR⁴ or N, A⁵ is CR⁵ or N, A⁶ is CR⁶ or Nand A⁸ is CR⁸ or N, provided that no more than one of A¹, A³, A⁴, A⁵, A⁶and A⁸ is N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹, A³ is CR³ or N, A⁴ is CR⁴ or N, A⁵ is CR⁵, A⁶ is CR⁶ and A⁸ is CR⁸,provided that no more than one of A³ and A⁴ is N, in conjunction withany of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹, A³ is N, A⁴ is CR⁴, A⁵ is CR⁵, A⁶ is CR⁶ and A⁸ is CR⁸, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹, A³ is CR³, A⁴ is N, A⁵ is CR⁵, A⁶ is CR⁶ and A⁸ is CR⁸, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹, A³ is CR³, A⁴ is CR⁴, A⁵ is CR⁵, A⁶ is CR⁶ and A⁸ is CR⁸, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ isCR¹, A³ is CR³ or N, A⁴ is CR⁴ or N, A⁵ is CR⁵, A⁶ is CR⁶ and A⁸ is CR⁸,wherein each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, Br, CF₃,OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkylportion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and—C(O)C₁₋₆-alkyl are optionally substituted with 1-3 substituents of F,oxo or OH and each of R³ and R⁶, independently, is H, halo, haloalkyl,haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl,NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl, provided that no more than one of A³ andA⁴ is N, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein A¹ is CHor CF, A³ is CH, CF or N, A⁴ is CH, CF or N, A⁵ is CH, CF or N, A⁶ isCH, CF or N, A⁸ is CH or CF, and R⁹ is H, CH₃, C₂H₅, propyl, butyl,acetyl or benzyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R¹ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein theC₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionally substituted with 1-3substituents of F, oxo or OH, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein R¹ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R¹ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R¹ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R¹ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R² isCl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or —Si(CH₃)₃,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R² isC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or —Si(CH₃)₃,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, phenyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-3 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R² isC₃₋₆-alkyl, C₃₋₈-cycloalkyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyranyl,tetrahydropyranyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,morpholinyl or 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, wherein theC₃₋₆-alkyl, C₃₋₈-cycloalkyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyranyl,tetrahydropyranyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,morpholinyl and 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl are optionallysubstituted, independently, with 1-3 substituents of R⁹, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R² isC₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, pyrimidyl, dihydropyranyl,tetrahydropyranyl, pyrrolidinyl, tetrahydropyrroly or piperidinyl,wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, pyrimidyl,dihydropyranyl, tetrahydropyranyl, pyrrolidinyl, tetrahydropyrroly andpiperidinyl are optionally substituted, independently, with 1-3substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R² isC₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, dihydropyranyl, pyrrolidinyl,tetrahydropyrrolyl or piperidinyl, wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl,pyridyl, dihydropyranyl, pyrrolidinyl, tetrahydropyrrolyl andpiperidinyl are optionally substituted, independently, with 1-3substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R² isC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl or —NH-benzyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl and —NH-benzyl are optionallysubstituted, independently, with 1-3 substituents of R⁹, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R² isCl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, or a ring selected fromphenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclobutyl, cyclopentyl or cyclohexyl, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionally substituted,independently, with 1-3 substituents of R⁹, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention includes compounds wherein R³ is H,halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl,S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R³ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl, —NHC₁₋₆-alkyl or—C(O)C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl areoptionally substituted with 1-3 substituents of F, oxo or OH, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R³ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R³ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R³ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R³ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁴ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein theC₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionally substituted with 1-3substituents of F, oxo or OH, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein R⁴ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁴ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁴ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁴ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁵ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein theC₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionally substituted with 1-3substituents of F, oxo or OH, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein R⁵ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁵ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁵ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁵ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁶ is H,halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl,S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁶ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein theC₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionally substituted with 1-3substituents of F, oxo or OH, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein R⁶ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁶ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁶ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁶ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isCl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NHC(═O)R⁹, —C(═O)NHR⁹,—NHS(O)₂R⁹, —S(O)₂NHR⁹, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isCl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isphenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or —Si(CH₃)₃, wherein the phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-3 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isC₂₋₄alkynyl, —OC₁₋₆alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl orpyridazinyl, wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, pyrimidyl,pyrazinyl and pyridazinyl are optionally substituted, independently,with 1-3 substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isC₂₋₄alkynyl, —OC₁₋₆alkyl, —NHC(═O)R⁹, —C(═O)NHR⁹, —NHS(O)₂R⁹,—S(O)₂NHR⁹, phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl,wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl, pyridyl, pyrimidyl, pyrazinyl andpyridazinyl are optionally substituted, independently, with 1-3substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁷ isC₂₋₄alkynyl, —OC₁₋₆alkyl, —NHC(═O)R⁹, —NHS(O)₂R⁹, phenyl, pyridyl,pyrimidyl, pyrazinyl or pyridazinyl, wherein the C₂₋₄alkynyl,—OC₁₋₆alkyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl areoptionally substituted, independently, with 1-3 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isC₂₋₄alkynyl, —OC₁₋₆alkyl, phenyl, 3-pyridyl, 5-pyrimidyl, pyrazinyl or2-pyridazinyl, wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl, 3-pyridyl,5-pyrimidyl, pyrazinyl and 2-pyridazinyl are optionally substituted,independently, with 1-3 substituents of R⁹, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ is aring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, said ringoptionally substituted, independently, with 1-3 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ is aring selected from phenyl, 3-pyridyl, 5-pyrimidyl or 2-pyridazinyl, saidring optionally substituted, independently, with 1-5 substituents of R⁹,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁷ isphenyl, 3-pyridyl, 5-pyrimidyl or 2-pyridazinyl, each of which isoptionally substituted with 1-5 substituents of F, Cl, Br, I, CN, CF₃,C₂F₅, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, SC₁₋₆-alkyl,oxetanyl or C₂₋₃alkynyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁸ is H,halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl,S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁸ is H,F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH, —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl, wherein theC₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl,—NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionally substituted with 1-3substituents of F, oxo or OH, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention includes compounds wherein R⁸ is H,F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁸ is H,F, methyl, CN or OH, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein R⁸ is Hor F, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein R⁸ is H,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein each R¹,R⁴, R⁵ and R⁸, independently, is F, Cl, CF₃, OCF₃, methyl, CN, OH, OCH₃,SCH₃, NHCH₃, oxetanyl or C₂₋₃alkynyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention includes compounds wherein each R⁹,independently, is F, CF₃, CN, CH₃, —OCH₃, —SCH₃, —NHCH₃, oxetanyl orC₂₋₃alkynyl, in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein each R⁹,independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, —C(O)NHCH₃,oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, morpholinyl, pyrazolyl, isoxazolyl,dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,oxetanyl or dioxolyl, wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkylamino-, C₁₋₆dialkylamino-,C₁₋₆alkoxyl, C₁₋₆thioalkoxyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, morpholinyl, pyrazolyl,isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, isoptionally substituted independently with 1-5 substituents of F, Cl, CN,NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,C₁₋₃alkylamino-, C₁₋₃dialkylamino, C₁₋₃thioalkoxyl, or oxetanyl, inconjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein —X—Y—taken together is —CR¹⁰R¹⁰—O—, —O—CR¹⁰R¹⁰—, —CR¹⁰R¹⁰—S— or —S—CR¹⁰R¹⁰,wherein each R¹⁰, independently, is H or F, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention includes compounds wherein —X—Y— is—CR¹⁰R¹⁰—O— or —O—CR¹⁰R¹⁰—, wherein each R¹⁰, independently, is H or F,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein —X—Y— is—CR¹⁰R¹⁰—S— or —S—CR¹⁰R¹⁰—, wherein each R¹⁰, independently, is H or F,in conjunction with any of the above or below embodiments.

In another embodiment, the invention includes compounds wherein —X—Y— is—CH₂—O— or —O—CH₂—, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein —X—Y— is—CH₂—S— or —S—CH₂—, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein —X—Y— is—CHF—O— or —O—CHF—, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention includes compounds wherein —X—Y— is—CF₂—O— or —O—CF₂—, in conjunction with any of the above or belowembodiments.

In another embodiment of the present invention, the compounds, andsolvates, hydrates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula I, wherein

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, CF₃, OCF₃,methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃;

one of R² and R⁷, independently, is phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or —Si(CH₃)₃,wherein the phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-3 substituents of R⁹;

the other of R² and R⁷, independently, is C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl or —NH-benzyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl and —NH-benzyl are optionally substituted, independently,with 1-3 substituents of R⁹;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆ alkyl, CN, OH, OC₁₋₆-alkyl, SC₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl; and

—X—Y— is —CR¹⁰R¹⁰—O—, —O—CR¹⁰R¹⁰—, —CR¹⁰R¹⁰—S— or —S—CR¹⁰R¹⁰, whereineach R¹⁰, independently, is H or F, in conjunction with any of the aboveor below embodiments.

In another embodiment of the present invention, the compounds, andsolvates, hydrates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula I, wherein

R² is halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, or a ring selected from phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionallysubstituted, independently, with 1-3 substituents of R¹⁰;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH;

each of R³ and R⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH,OCH₃, SCH₃ or NHCH₃;

R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thiophenyl, said ring optionally substituted,independently, with 1-3 substituents of R¹⁰; and

—X—Y— is —CH₂—O— or —O—CH₂—, in conjunction with any of the above orbelow embodiments.

In another embodiment of the present invention, the compounds, andsolvates, hydrates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula II, wherein

R¹ is H or F;

A³ is CH, CF or N;

A⁴ is CH, CF or N;

R⁵ is H or F;

A⁶ is CH, CF or N;

R⁸ is H or F; and

—X—Y— is —CH₂—O— or —O—CH₂—, in conjunction with any of the above orbelow embodiments.

In another embodiment of the present invention, the compounds, andsolvates, hydrates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula II, wherein

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, CF₃, OCF₃,methyl, ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃;

one of R² and R⁷, independently, is phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or —Si(CH₃)₃,wherein the phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-3 substituents of R¹⁰;

the other of R² and R⁷, independently, is C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl or —NH-benzyl, wherein the C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂,—NH-phenyl and —NH-benzyl are optionally substituted, independently,with 1-3 substituents of R¹⁰;

each of R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, SC₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl; and

—X—Y— is —CH₂—O—, —O—CH₂—, —CH₂—S— or —S—CH₂—, in conjunction with anyof the above or below embodiments.

In another embodiment of the present invention, the compounds, andsolvates, hydrates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula II, wherein

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, or a ring selectedfrom phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionallysubstituted, independently, with 1-3 substituents of R⁹;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH;

each of R³ and R⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH,OCH₃, SCH₃ or NHCH₃;

R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thienyl, said ring optionally substituted,independently, with 1-3 substituents of R⁹; and

—X—Y— is —CH₂—O— or —O—CH₂—, in conjunction with any of the above orbelow embodiments.

In another embodiment of the present invention, the compounds, andsolvates, hydrates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula II, wherein

A³ is CR³ or N;

A⁴ is CR⁴;

R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, or a ring selectedfrom phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionallysubstituted, independently, with 1-3 substituents of R⁹;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH;

each of R³ and R⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH,OCH₃, SCH₃ or NHCH₃;

R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thienyl, said ring optionally substituted,independently, with 1-3 substituents of R⁹; and

—X—Y— is —CH₂—O— or —O—CH₂—.

In another embodiment of the present invention, the compounds, andsolvates, hydrates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula II, wherein

A³ is N;

A⁴ is CR⁴;

R² is halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, or a ring selected from phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionallysubstituted, independently, with 1-3 substituents of R¹⁰;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH;

R⁶ is H, F, Cl, CF₃, methyl, CN, OH, OCH₃, SCH₃ or NHCH₃;

R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thiophenyl, said ring optionally substituted,independently, with 1-3 substituents of R⁹; and

—X—Y— is —CH₂—O— or —O—CH₂—.

In another embodiment of the present invention, the compounds, andsolvates, hydrates, tautomers, stereoisomers and pharmaceuticallyacceptable salts thereof, are defined by Formula II, wherein

A³ is CR³;

A⁴ is CR⁴ or N;

R² is halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, or a ring selected from phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionallysubstituted, independently, with 1-3 substituents of R¹⁰;

each of R¹, R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH;

each of R³ and R⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH,OCH₃, SCH₃ or NHCH₃;

R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thiophenyl, said ring optionally substituted,independently, with 1-3 substituents of R⁹; and

—X—Y— is —CH₂—O— or —O—CH₂—.

In another embodiment, the invention provides one or more of thecompounds, or a pharmaceutically acceptable salt thereof, of Formulas I,II, III and IV, as taught and described herein.

In another embodiment, the invention provides the compound of Formula I,II, II-A, III or IV, or a stereoisomer or pharmaceutically acceptablesalt thereof, selected from

-   (5R/S)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)-6′,7′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine;-   (5R)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)-6′,7′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine;-   (5S)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)-6′,7′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine;-   (5S)-7-bromo-3-chloro-6′,7′-dihydro    spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine;-   (5R)-7-bromo-3-chloro-6′,7′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine;-   (3R/S)-2′-(2,2-dimethylpropoxy)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-6,7-dihydrospiro[1,4-oxazepine-3,9′-xanthen]-5-amine;-   (3S)-2′-(2,2-dimethylpropoxy)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-6,7-dihydrospiro[1,4-oxazepine-3,9′-xanthen]-5-amine;-   (3R)-2′-(2,2-dimethylpropoxy)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-6,7-dihydrospiro[1,4-oxazepine-3,9′-xanthen]-5-amine;    and-   (5R)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine.

All of the possible embodiments described herein for various of the R, Xand Y groups of the compounds of Formula I may be applied, asappropriate, to compounds of Formulas II, III and IV, and anysub-formulas thereof.

In another embodiment, the invention provides each of the Examplarycompounds, and stereoisomers, tautomers, solvates, pharmaceuticallyacceptable salts thereof, and related intermediates, described herein.

In another embodiment, the invention provides the exemplified compoundsdescribed herein, and stereoisomers and pharmaceutically acceptable saltforms of each thereof.

DEFINITIONS

The following definitions should assist in understanding the invention.

The term “comprising” is meant to be open ended, i.e., all encompassingand non-limiting. It may be used herein synonymously with “having” or“including.” Comprising is intended to include each and every indicatedor recited component or element(s) while not excluding any othercomponents or elements.

The term “C_(α-β)alkyl”, when used either alone or within other termssuch as “haloalkyl” and “alkylamino”, embraces linear or branchedhydrocarbon radicals having α to β number of carbon atoms (such asC₁-C₁₀; C₁-C₆; or C₁-C₄). Unless otherwise specified, one or more carbonatoms of the “alkyl” radical may be substituted, such as with an —OH, CNor cycloalkyl moiety. Examples of “alkyl” radicals include methyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, ethyl,cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, n-propyl,isopropyl, n-butyl, cyclopropylbutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isoamyl, hexyl and the like.

The term “C_(α-β)alkenyl”, when used alone or in combination, embraceslinear or branched hydrocarbon radicals having at least onecarbon-carbon double bond in a moiety having a number of carbon atoms inthe range from α and β. Included within alkenyl radicals are “loweralkenyl” radicals having two to about six carbon atoms and, for example,those radicals having two to about four carbon atoms. Examples ofalkenyl radicals include, without limitation, ethenyl, propenyl, allyl,propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “loweralkenyl”, embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations, as appreciated by those ofordinary skill in the art.

The term “C_(α-β)alkynyl”, when used alone or in combination, denoteslinear or branched hydrocarbon radicals having at least onecarbon-carbon triple bond in a moiety having a number of carbon atoms inthe range from α and β. Examples of alkynyl radicals include “loweralkynyl” radicals having two to about six carbon atoms and, for example,lower alkynyl radicals having two to about four carbon atoms. Examplesof such radicals include, without limitation, ethynyl, propynyl(propargyl), butynyl, and the like.

The term “C_(α-β)-alkyl”, “C_(α-β)-alkenyl” and “C_(α-β)-alkynyl”, whenused with other terms such as “wherein 1, 2 or 3 carbon atoms of saidC_(α-β)-alkyl, C_(α-β)-alkenyl or C_(2α-β)-alkynyl is optionallyreplaced with a heteroatom selected from O, S, S(O), S(O)₂ and N”embraces linear or branched radicals wherein one or more of the carbonatoms may be replaced with a heteroatom. Examples of such “alkyl”radicals include O-methyl, —O-ethyl, —CH₂—O—CH₃, —CH₂CH₂—O—CH₃, —NH—CH₂,—CH₂CH₂—N(CH₃)—CH₃, —S—(CH₂)₃CH₂, —CH₂CH₂—S—CH₃ and the like.Accordingly, such radicals also include radicals encompassed by —OR⁷where R⁷ may be defined as a C_(α-β)-alkyl. Examples of such “alkenyl”radicals include —NH—CH₂CH═CH₂, —S—CH₂CH₂CH═CHCH₃ and the like. Similarexamples exist for such “alkynyl” radicals, as appreciated by thoseskilled in the art.

The term “C_(α-β)alkoxyl” or “—OC_(α-β)alkyl” when used alone or incombination, embraces linear or branched oxygen-containing alkylradicals each having α to β number of carbon atoms (such as C₁-C₁₀). Theterms “alkoxy” and “alkoxyl”, when used alone or in combination,embraces linear or branched oxygen-containing radicals each having alkyland substituted alkyl portions of one or more carbon atoms. Examples ofsuch radicals include methoxy, ethoxy, propoxy, butoxy, tert-butoxy andneopentoxy. Alkoxy radicals may be further substituted with one or morehalo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy”radicals or with other substitution. Examples of such radicals includefluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,fluoroethoxy and fluoropropoxy.

The term “aryl”, when used alone or in combination, means a carbocyclicaromatic moiety containing one, two or even three rings wherein suchrings may be attached together in a fused manner. Every ring of an“aryl” multi-ring system need not be aromatic, and the ring(s) fused tothe aromatic ring may be partially or fully unsaturated and include oneor more heteroatoms selected from nitrogen, oxygen and sulfur. Thus, theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,benzodioxazinyl, and the like. The “aryl” group may be substituted, suchas with 1 to 5 substituents including lower alkyl, hydroxyl, halo,haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the like.Phenyl substituted with —O—CH₂—O— or —O—CH₂—CH₂—O— forms an arylbenzodioxolyl substituent.

The term “C_(α-β)-cycloalkyl”, also referred to herein as “carbocyclic”,when used alone or in combination, denotes a partially or fullysaturated ring radical having a number of carbon atoms in the range fromα and β. The “cycloalkyl” may contain one (“monocyclic”), two(“bicyclic”) or even three (“tricyclic”) rings wherein such rings may beattached together in a fused manner and each formed from carbon atoms.Examples of saturated carbocyclic radicals include saturated 3 to6-membered monocyclic groups such as cyclopropane, cyclobutane,cyclopentane and cyclohexane. Cycloalkyls may be substituted asdescribed herein.

The terms “ring” and “ring system” refer to a ring comprising thedelineated number of atoms, the atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. Where the number ofatoms is not delineated, such as a “monocyclic ring system” or a“bicyclic ring system”, the numbers of atoms are 3-8 for a monocyclicand 6-12 for a bicyclic ring. The ring itself, as well as anysubstitutents thereon, may be attached at any atom that allows a stablecompound to be formed. The term “nonaromatic” ring or ring system refersto the fact that at least one, but not necessarily all, rings in abicyclic or tricyclic ring system is nonaromatic.

The terms “partially or fully saturated or unsaturated” and “saturatedor partially or fully unsaturated” with respect to each individual ring,refer to the ring either as fully aromatic (fully unsaturated),partially aromatic (or partially saturated) or fully saturated(containing no double or triple bonds therein). If not specified assuch, then it is contemplated that each ring (monocyclic) in a ringsystem (if bicyclic or tricyclic) may either be fully aromatic,partially aromatic or fully saturated, and optionally substituted withup to 5 substituents. This includes carbocyclics, heterocyclics, aryland heteroaryl rings.

The term “halo”, when used alone or in combination, means halogens suchas fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms.

The term “haloalkyl”, when used alone or in combination, embracesradicals wherein any one or more of the hydrogen atoms on the alkylradical is replaced with a halo as defined above. For example, this termincludes monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as aperhaloalkyl. A monohaloalkyl radical, for example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. Examples of haloalkyl radicalsinclude fluoromethyl, difluoromethyl, trifluoromethyl (—CF₃),chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Perfluoroalkyl”, as used herein, refers to alkyl radicals having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

The term “heteroaryl”, as used herein, either alone or in combination,means a fully unsaturated (aromatic) ring moiety formed from carbonatoms and having one or more heteroatoms selected from nitrogen, oxygenand sulfur. The ring moiety or ring system may contain one(“monocyclic”), two (“bicyclic”) or even three (“tricyclic”) ringswherein such rings are attached together in a fused manner. Every ringof a “heteroaryl” ring system need not be aromatic, and the ring(s)fused thereto (to the heteroaromatic ring) may be partially or fullysaturated and optionally include one or more heteroatoms selected fromnitrogen, oxygen and sulfur. The term “heteroaryl” does not includerings having ring members of —O—O—, —O—S— or —S—S—.

Examples of heteroaryl radicals include unsaturated 5- to 6-memberedheteromonocyclyl groups containing 1 to 4 nitrogen atoms, including forexample, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] andtetrazole; unsaturated 7- to 10-membered heterobicyclyl groupscontaining 1 to 4 nitrogen atoms, including for example, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and thelike; unsaturated 5- to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The terms “heterocycle” or “heterocyclic”, when used alone or incombination, means a partially or fully saturated ring moiety containingone, two or even three rings wherein such rings may be attached togetherin a fused manner, formed from carbon atoms and including one or moreheteroatoms selected from N, O or S. Examples of saturated heterocyclicradicals include saturated 3 to 6-membered heteromonocyclic groupscontaining 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl,piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturatedheterocyclyl radicals include dihydrothienyl, dihydropyranyl,dihydrofuryl and dihydrothiazolyl.

The term “heterocycle” also embraces radicals where heterocyclicradicals are fused/condensed with aryl radicals: unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals.

Examples of partially saturated and fully saturated heterocyclylsinclude, without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted” refers to a single ring of 3-, 4-, 5-, 6-, 7- or8-atom membered or a 6-, 7-, 8-, 9-, 10-, 11 or 12-atom memberedbicyclic ring system comprising the delineated number of atoms, theatoms being carbon or, where indicated, a heteroatom such as nitrogen(N), oxygen (O) or sulfur (S). Where the number of atoms is notdelineated, such as a “monocyclic ring system” or a “bicyclic ringsystem”, the numbers of atoms are 3-8 for a monocyclic and 6-12 for abicyclic ring. The ring or ring system may contain substitutentsthereon, attached at any atom that allows a stable compound to beformed. A bicyclic ring is intended to include fused ring systems aswell as spiro-fused rings. This phrase encompasses carbocyclics,heterocyclics, aryl and heteroaryl rings.

The term “alkylamino” includes “N-alkylamino” where amino radicals areindependently substituted with one alkyl radical. Preferred alkylaminoradicals are “lower alkylamino” radicals having one to six carbon atoms.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Examples of such lower alkylamino radicals includeN-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and thelike.

The term “dialkylamino” includes “N,N-dialkylamino” where amino radicalsare independently substituted with two alkyl radicals. Preferredalkylamino radicals are “lower alkylamino” radicals having one to sixcarbon atoms. Even more preferred are lower alkylamino radicals havingone to three carbon atoms. Examples of such lower alkylamino radicalsinclude N,N-dimethylamino, N,N-diethylamino, and the like.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—. “Carbonyl” is also used hereinsynonymously with the term “oxo”.

The term “alkylthio” or “thioalkoxy” embraces radicals containing alinear or branched alkyl radical, of one to ten carbon atoms, attachedto a divalent sulfur atom. An example of “alkylthio” or “thioalkoxy” ismethylthio, (CH₃S—).

The term “Formula I” includes any sub formulas, such as Formulas II, IIIand IV. Similar with Formulas II, III and IV, in that they includesub-formulas where described.

The term “pharmaceutically-acceptable” when used with reference to acompound of Formulas I-IV is intended to refer to a form of the compoundthat is safe for administration. For example, a salt form, a solvate, ahydrate, a prodrug or derivative form of a compound of Formulas I-IV,which has been approved for mammalian use, via oral ingestion or otherroutes of administration, by a governing body or regulatory agency, suchas the Food and Drug Administration (FDA) of the United States, ispharmaceutically acceptable.

Included in the compounds of Formulas I-IV are the pharmaceuticallyacceptable salt forms of the free-base compounds. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. As appreciated by those of ordinary skill in the art, salts maybe formed from ionic associations, charge-charge interactions, covalentbonding, complexation, coordination, etc. The nature of the salt is notcritical, provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds ofFormulas I-IV may be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, hydrofluoric, nitric, carbonic, sulfuric and phosphoricacid. Appropriate organic acids may be selected from aliphatic,cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic andsulfonic classes of organic acids, examples of which include, withoutlimitation, formic, acetic, adipic, butyric, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,thiocyanic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formulas I-III include metallicsalts, such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases including,without limitation, primary, secondary and tertiary amines, substitutedamines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, disopropylethylamine and trimethylamine. All of thesesalts may be prepared by conventional means from the correspondingcompound of the invention by reacting, for example, the appropriate acidor base with the compound of Formulas I-IV.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66:1 (1977). Conventional methods may be used to form thesalts. For example, a phosphate salt of a compound of the invention maybe made by combining the desired compound free base in a desiredsolvent, or combination of solvents, with phosphoric acid in a desiredstoichiometric amount, at a desired temperature, typically under heat(depending upon the boiling point of the solvent). The salt can beprecipitated upon cooling (slow or fast) and may crystallize (i.e., ifcrystalline in nature), as appreciated by those of ordinary skill in theart. Further, hemi-, mono-, di, tri- and poly-salt forms of thecompounds of the present invention are also contemplated herein.Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of thecompounds, salts and derivatives thereof, are also contemplated herein.

The term “pharmaceutically-acceptable derivative” as used herein,denotes a derivative which is pharmaceutically acceptable.

The compound(s) of Formulas I-IV may be used to treat a subject byadministering the compound(s) as a pharmaceutical composition. To thisend, the compound(s) can be combined with one or more excipients,including without limitation, carriers, diluents or adjuvants to form asuitable composition, which is described in more detail herein.

The term “excipient”, as used herein, denotes any pharmaceuticallyacceptable additive, carrier, adjuvant, or other suitable ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration purposes.“Diluent” and “adjuvant” are defined hereinafter.

The terms “treat”, “treating,” “treatment,” and “therapy” as used hereinrefer to therapy, including without limitation, curative therapy,prophylactic therapy, and preventative therapy. Prophylactic treatmentgenerally constitutes either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals.

The phrase “effective dosage amount” is intended to quantify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies. Accordingly, this term is not limited to a singledose, but may comprise multiple dosages required to bring about atherapeutic or prophylactic response in the subject. For example,“effective dosage amount” is not limited to a single capsule or tablet,but may include more than one capsule or tablet, which is the doseprescribed by a qualified physician or medical care giver to thesubject.

The term “leaving group” (also denoted as “LG”) generally refers togroups that are displaceable by a nucleophile. Such leaving groups areknown in the art. Examples of leaving groups include, but are notlimited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate,tosylate), sulfides (e.g., SCH₃), N-hydroxsuccinimide,N-hydroxybenzotriazole, and the like. Nucleophiles are species that arecapable of attacking a molecule at the point of attachment of theleaving group causing displacement of the leaving group. Nucleophilesare known in the art. Examples of nucleophilic groups include, but arenot limited to, amines, thiols, alcohols, Grignard reagents, anionicspecies (e.g., alkoxides, amides, carbanions) and the like.

General Synthetic Procedures

The present invention further comprises procedures for the preparationof compounds of Formulas I-IV. The compounds of Formulas I-IV can besynthesized according to the procedures described in the followingSchemes 1, 2, 3a, 3b, 4 and 5, wherein the substituents are as definedfor Formulas I-IV above, except where further noted. The syntheticmethods described below are merely exemplary, and the compounds of theinvention may also be synthesized by alternate routes utilizingalternative synthetic strategies, as appreciated by persons of ordinaryskill in the art.

The following list of abbreviations used throughout the specificationrepresent the following and should assist in understanding theinvention:

-   ACN, MeCN—acetonitrile-   Aq., aq.—aqueous-   Ar—argon (gas)-   BOP—benzotriazol-1-yl-oxy Hexafluorophosphate-   BuLi—Butyllithium-   Cs₂CO₃—cesium carbonate-   CHCl₃—chloroform-   CH₂Cl₂, DCM—dichloromethane, methylene chloride-   Cu(1)I—copper(1) iodide-   DCC—dicyclohexylcarbodiimide-   DEA—diethylamine-   DIC—1,3-diisopropylcarbodiimide-   DIEA, DIPEA—diisopropylethylamine-   DME—dimethoxyethane-   DMF—dimethylformamide-   DMAP—4-dimethylaminopyridine-   DMSO—dimethylsulfoxide-   EDC, EDCI—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   G, gm—gram-   h, hr—hour-   H₂—hydrogen (gas)-   H₂O—water-   HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   HBr—hydrobromic acid-   HCl—hydrochloric acid-   HOBt—1-hydroxybenzotriazole hydrate-   HOAc—acetic acid-   HPLC—high pressure liquid chromatography-   IPA, IpOH—isopropyl alcohol-   K₂CO₃—potassium carbonate-   KI—potassium iodide-   LG—leaving group-   LDA—Lithium diisopropylamide-   LiOH—lithium hydroxide-   MgSO₄—magnesium sulfate-   MS—mass spectrum-   MeOH—methanol-   N₂—nitrogen (gas)-   NaCNBH₃—sodium cyanoborohydride-   Na₂CO₃—sodium carbonate-   NaHCO₃—sodium bicarbonate-   NaH—sodium hydride-   NaI—sodium iodide-   NaBH₄—sodium borohydride-   NaOH—sodium hydroxide-   Na₂SO₄—sodium sulfate-   NH₄Cl—ammonium chloride-   NH₄OH—ammonium hydroxide-   P(t-bu)₃—tri(tert-butyl)phosphine-   Pd/C—palladium on carbon-   Pd(PPh₃)₄—palladium(0)triphenylphosphine tetrakis-   Pd(dppf)Cl₁₂—palladium(1,1-bisdiphenylphosphinoferrocene) II    chloride-   Pd(PhCN)₂Cl₂—palladium di-cyanophenyl dichloride-   Pd(OAc)₂—palladium acetate-   Pd₂(dba)₃—tris(dibenzylideneacetone) dipalladium-   PyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium    hexafluorophosphate-   RT, rt—room temperature-   RBF, rbf—round bottom flask-   TLC, tic—thin layer chromatography-   TBAF—Tetrabutylammonium flouride-   TBTU—O-benzotriazol-1-yl-N,N,N,N′-tetramethyluronium    tetrafluoroborate-   TEA, Et₃N—triethylamine-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran-   UV—ultraviolet light

Scheme 1 describes an exemplary method for preparing racemic compounds10 of Formulas I, II, III and IV, wherein A¹, A⁵, A⁶ and A⁸ are each CHand either of A³ and A⁴ maybe CR³ or N or CR⁴ or N, respectively, andwherein Y is —O— and X is CH₂. One can start by reactingchloro-hydroxy-pyridine or chloro-phenol with 2,5-dibromobenzoic acid inthe presence of a suitable base, such as cesium carbonate as shownabove, to afford the ether linked adduct 2. The carboxylic acid of 2 maythen be functionalized to the corresponding amide 3 under suitableconditions, such as those described herein, and treated with a strongbase, such as LDA, to provide the corresponding ketone intermediate 4.

The intermediate 4 and similar intermediates may also be prepared inaccordance to that described in PCT published patent applicationWO2010030954, pages 51, Scheme 1, compounds 1-4 and Example 1 on pg 59,lines 17-pg 60, line 10, each section of which is expressly incorporatedherein by reference.

Ketone 4 can then be treated with a strong base, such as potassiumt-butoxide, in the presence of trimethylsilane and trimethylsilylazide,as described above, to afford the azido-intermediate 5, which isgenerated in-situ and not isolated. The reactive azide 5 can be treatedwith a strong base, such as LAH as shown, to provide the correspondingamino-alcohol intermediate 6. The alcohol can then be converted to thecorresponding ethyl-cyano ether moiety in compound 7, as describedherein. The cyano-ether 7 can be cyclized to close the oxezapine ringand afford intermediate 8, using conventional methods, such as withtrimethyl-aluminum, under the conditions shown above and describedherein.

Intermediate 8 is an important intermediate as is allows one to preparedesired compounds of the invention with varied substituent groups ateach of the R² and R⁷ connections. For example, asn as shown above,desired R⁷ moieties may be installed on intermediate 8 usingconventional boronic acid chemistry, such as using Suzuki and similarconditions to attach a desired aromatic ring at R⁷, to provideintermediate 9. Similarly, intermediate 9 may then be subjected to asecond Suzuki or like boronic acid chemistry to afford the compounds ofthe invention 10.

The boronic acid, or boronic ester, intermediates utilized in stepsabove may be prepared by methods described in the following references:(1) PCT Int. Patent Appl. No. WO 2005073189, titled “Preparation offused heteroaryl derivatives as p38 kinase inhibitors” or (2) PCT Int.Patent Appl. No. WO 2006094187, titled “Preparation of phthalazine, aza-and diaza-phthalazine compounds as protein kinase, especially p38kinase, inhibitors for treating inflammation and related conditions”.Also, desired boronic acids may be purchased commercially from vendorcatalogs, such as from ASigma-Aldrich Chemicals for instance, orspecially made by the vendor or by persons of ordinary skill in the art.

The Suzuki method is a reaction using a borane reagent, such as aboronic acid or ester such as a dioxaborolane, and a suitable leavinggroup containing reagent, such as the bromo-xanthene 4 (halogens,including bromides and chlorides are suitable halogen leaving groups“LG”). As appreciated to one of ordinary skill in the art, Suzukireactions also utilize a palladium catalyst. Suitable palladiumcatalysts include, without limitation, Pd(PPh₃)₄, Pd(OAc)₂ orPd(dppf)Cl₂. Where LG is a halide, the halide may be an iodide, abromide or chloride. Chloro-pyridyl rings (where either of A³ or A⁴=N)undergo Suzuki reactions in the presence of Pd catalysts. Other LGs arealso suitable. For example, Suzuki couplings are known to occur with asulfonate, such as trifluoromethanesulfonate, as the leaving group.

The Suzuki reaction conditions may vary. For example, Suzuki reactionsare generally run in the presence of a suitable base such as a carbonatebase, bicarbonate or an acetate base, in a suitable solvent such astoluene, acetonitrile, DMF or an aqueous-organic solvent combination ora biphasic system of solvents. Further, the reaction may require heatdepending upon the particular bromide 4 and/or boronic acid or ester, asappreciated by those skilled in the art. In addition, where the bromideis an aromatic moiety, such as phenyl, the reaction may be complete in ashort period of time with heat.

Other coupling methods are known. For example metal catalized couplingchemistry, such Stille, Kumada, Negishi coupling methods, and the like,may be employed to the xanthene cores 4 to prepare desired cyclicproducts 8. In addition, compounds may possess groups which may need tobe protected (and later deprotected), such as a free amino group, tocarry out effective coupling reactions to install either R² or R⁷ groupsto afford the final desired compounds 10, as appreciated by persons ofordinary skill in the art.

Scheme 2 describes an exemplary method for preparing racemic compounds20 of Formulas I, II, III and IV, wherein A¹, A⁵, A⁶ and A⁸ are each CHand either of A³ and A⁴ maybe CR³ or N or CR⁴ or N, respectively, andwherein Y is —O— and X is CH₂. One can start by reactingmethoxy-hydroxy-pyridine or 4-methoxy-phenol with 2,5-dibromobenzoicacid in the presence of a suitable base, such as cesium carbonate asshown above, to afford the ether linked adduct 12. The carboxylic acidof 12 may then be functionalized to the corresponding amide 13 undersuitable conditions, such as those described herein, and treated with astrong base, such as LDA, to provide the corresponding ketoneintermediate 14.

The intermediate 13 and similar intermediates may also be prepared inaccordance to that described in PCT published patent applicationWO2010030954, pages 53, Scheme 2, compounds 9-13; Scheme 3b on pg 55,compound 32; Example 1 on pg 59, lines 17-pg 60, line 10; Example 3 onpg 62; and Example 5-7 beginning on pg 65 of WO2010030954, eachdisclosure of which is expressly incorporated herein by reference.

Ketone 3 can then be treated with a strong base, such as potassiumt-butoxide, in the presence of trimethylsilane and trimethylsilylazide,as described above, to afford the azido-intermediate 4, which isgenerated in-situ and not isolated. The reactive azide 4 can be treatedwith a strong base, such as LAH as shown, to provide the correspondingamino-alcohol intermediate 5. The alcohol can then be converted to thecorresponding ethyl-cyano ether moiety in compound 6, as describedherein. The cyano-ether 6 can be cyclized to close the oxezapine ringand afford intermediate 17, using conventional methods, such as withtrimethyl-aluminum, under the conditions shown above and describedherein. The methoxyl group of intermediate 17 can be reduced to thecorresponding hydroxyl group intermediate 18 using known reagents, suchas BBr₃, under suitable conditions, such as those described herein andin WO2010030954.

Intermediate 18 is an important intermediate as is allows one to preparedesired compounds of the invention with varied substituent groups ateach of the R² and R⁷ connections. For example, and as shown above,desired R⁷ moieties may be installed on intermediate 18 usingconventional Suzuki coupling methods via coupling at the site of thebromide, or Suzuki-like aromatic-halogen exchange reactions, whichreactions generally employ a boronic acid moiety, a palladium catalystreagent and a base. Other aryl/heteroaryl coupling methods, includingStille and the like under appropriate conditions, may also be employedto provide compounds 19. Similarly, intermediate 19 may then besubjected to a suitable base, such as cesium carbonate, followed bytreatment with a desired alkyl-R² group to afford the O-linked R²compounds of the invention 20.

Alternatively, the hydroxyl group of compound 19 can be activated into asuitable leaving group (“LG” in scheme 1), such as a triflate, as knownin the art and described in the literature, or other suitable O-linkedleaving group. The leaving group of intermediate 19 (not shown) can thenbe reacted with a desired aromatic boronic acid to install the desiredR² group, as shown in scheme 1, to afford the desired compounds 20 ofFormulas I-IV.

Desired compounds 21 of Formulas I, II, III and IV, and sub-formulasthereof, wherein the R² group is —OR may be made as generally describedin Scheme 3. As shown, R⁷-hydroxy intermediate 19a can be functionalizedas desired, such as by alkylation as shown, by reaction with an alkylhalide 12 in the presence of a suitable base, such as cesium carbonate,in suitable solvents to afford the finally desired product 21.

“LG” in this instance is a “leaving group” which may be a halide such asan iodide, bromide, chloride or fluoride. LG may also be a non-halidemoiety such as an alkylsulfonate or other known groups which generallyform an electrophilic species (E⁺). Coupling reactions generally occurmore readily in one or a combination of solvents and a base. Suitablesolvents include, without limitation, generally non-nucleophilic,anhydrous solvents such as toluene, CH₂Cl₂, THF, DMF,N,N-dimethylacetamide and the like. The solvent may range in polarity,as appreciated by those skilled in the art. Suitable bases include, forexample, tertiary amine bases such as DIEA, TEA, carbonate bases such asNa₂CO₃, K₂CO₃, Cs₂CO₃, hydrides such as NaH, KH and the like, alkoxidessuch as NaOCH₃, and the like. The base itself may also serve as asolvent. These coupling reactions are generally fast and conversionoccurs typically in ambient conditions. However, depending upon theparticular substrate, such reactions may require heat, as appreciated bythose skilled in the art.

Scheme 4 describes an exemplary method for preparing racemic thiazepanecompounds 25 of Formulas I, II, III and IV, wherein A¹, A⁵, A⁶ and A⁸are each CH and either of A³ and A⁴ maybe CR³ or N or CR⁴ or N,respectively, and wherein Y is —S— and X is CH₂. Generally, thiazepanecompounds 25 (where either of X or Y is —S— and the other is CH₂) may beprepared by the relevant conditions and methods described in K.Shankaran et al. Bioorg. Med. Chem. Lett. (2004) 14 (23), 5907-5911.

As shown and described in scheme 1 above, the amino-alcohol intermediate6 may be used in scheme 4. The amine group of intermediate 6 may beprotected using conventional protection groups, such as BOC-anhydride asshown, followed by formation of intermediate 22 by activating thealcohol group in 6 and displacing it with the BOC-protected amine. Thecyclic amine may be opened with mercaptoproprionic acid in the presenceof a suitable base, such as cesium carbonate, to form the correspondingmercapto linker (not shown). The amine may then be deprotected using asuitable acid, such as HCl, and the acid in the mercapto linker can beactivated using conventional activating groups, such as EDC in thepresence of a suitable base, to provide the corresponding ring closedlactam 23. Lactam 23 may then be converted to the corresponding primaryamine 24 using known methods, such as with Lawesson's Reagent as shownin scheme 4.

Chloro-Bromo-Intermediate 24 is an important intermediate as is allowsone to prepare desired compounds of the invention with variedsubstituent groups at each of the R² and R⁷ connections. For example,and as shown above in schemes 1 and 2, desired R⁷ moieties may beinstalled on intermediate 24 using conventional boronic acid chemistry,such as using Suzuki and similar conditions to attach a desired aromaticring at R⁷, to provide a further intermediate (not shown). Similarly,the latter intermediate may then be subjected to a second Suzuki or likeboronic acid chemistry to afford the compounds of the invention 25.

Scheme 5 describes an exemplary method for preparing racemic thiazepanecompounds 29 of Formulas I, II, III and IV, wherein A¹, A⁵, A⁶ and A⁸are each CH and either of A³ and A⁴ maybe CR³ or N or CR⁴ or N,respectively, and wherein X is —S— and Y is CH₂. Generally, thiazepanecompounds 29 (where either of X or Y is —S— and the other is CH₂) may beprepared by the relevant conditions and methods described in K.Shankaran et al. Bioorg. Med. Chem. Lett. (2004) 14 (23), 5907-5911.

As shown and described in scheme 1 above, thechloro-bromo-aza-xanthene-ketone intermediate 4 may be used in scheme 5.The ketone group of intermediate 4 may be subjected to reductiveamination using the sulfonamide as shown above under suitableconditions, followed by reaction with t-butoxy-2-oxoethyl-zinc-chlorideto afford the corresponding t-butyl ester (not shown). The ester maythen be reduced down to the corresponding alcohol, using conventionalmethods, such as using DIBAL. The amine group can then be protectedusing conventional protection groups, such as BOC-anhydride as shown,followed by a Mitsunobu reaction wherein the primary alcohol can beconverted to the corresponding iodide using standard Mitsunobuconditions, such as triphenylphosphine and a source of iodine, toprovide intermediate 26. The iodo group can then be reacted with2-mercaptoacidic acid to install the sulfide linkage ending with an acidgroup (not shown). The amine may then be deprotected using a suitableacid, such as HCl, and the acid group can be activated, similar to thatdescribed in scheme 4 above, and displaced with deprotected amine toafford the ring closed thiazepane lactam 27. Lactam 27 may then beconverted to the corresponding primary amine 28 using known methods,such as with Lawesson's Reagent as shown in scheme 4.

Chloro-Bromo-Intermediate 28 is an important intermediate as is allowsone to prepare desired compounds of the invention with variedsubstituent groups at each of the R² and R⁷ connections. For example,and as shown above in schemes 1 and 2, desired R⁷ moieties may beinstalled on intermediate 28 using conventional boronic acid chemistry,such as using Suzuki and similar conditions to attach a desired aromaticring at R⁷, to provide a further intermediate (not shown). Similarly,the latter intermediate may then be subjected to a second Suzuki or likeboronic acid chemistry to afford the compounds of the invention 29.

Desired compounds 33 of Formulas I-II, and sub-formulas thereof whereinR⁷ is an amide or sulfonamide linker to desired R⁹ groups may be made asgenerally described in Scheme 6. As shown, desired R⁹ amines may becoupled directed to the bromide intermediate 30 using XPhos in thepresence of a suitable palladium catalyst under suitable conditions toafford desired products 31.

Similarly, compound 30 can be transformed into the corresponding amine32 using conditions like those described in scheme 1 hereinabove.Compound 32 may then be reacted with a desired acid in the presence ofconventional amide coupling conditions to afford desired compound 33.Alternatively the R⁹-acid may be converted to the correspondingacid-halide, such as a reactive acid-chloride using oxalyl chlorideunder suitable conditions, and reacted with the amine 32 in the presenceof a suitable base and solvent to afford product 33.

EXAMPLES

The Examples, described herein below, represent various exemplarystarting materials, intermediates and compounds of Formulas I-IV, whichshould assist in a better understanding and appreciation of the scope ofthe present invention and of the various methods that may be used tosynthesize compounds of Formulas I-IV. Starting materials andintermediates used in the Examples herein may also be prepared using theprocedures described in co-pending U.S. patent application Ser. No.12/558,426, filed Sep. 11, 2009, which specification and disclosure ishereby incorporated herein by reference in its entirety. It should beappreciated that the general methods above and specific examples beloware illustrative only, for the purpose of assistance and ofunderstanding the present invention, and should not be construed aslimiting the scope of the present invention in any manner.

Chromatography:

Unless otherwise indicated, crude product-containing residues werepurified by passing the crude material or concentrate through either aBiotage or Isco brand silica gel column (pre-packed or individuallypacked with SiO₂) and eluting the product off the column with a solventgradient as indicated. For example a description of (330 g SiO₂, 0-40%EtOAc/Hexane) means the product was obtained by elution from the columnpacked with 330 gms of silica, with a solvent gradient of 0% to 40%EtOAc in Hexanes.

Preparative HPLC Method:

Unless otherwise indicated, the compounds described herein were purifiedvia reverse phase HPLC using one of the following instruments: Shimadzu,Varian, Gilson; utilizing one of the following two HPLC columns: (a) aPhenomenex Luna or (b) a Gemini column (5 micron or 10 micron, C18,150×50 mm)

A typical run through the instrument included: eluting at 45 ml/min witha linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water(0.1% TFA) over 10 minutes; conditions can be varied to achieve optimalseparations.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Brukerseries 300 MHz instrument or a Bruker series 400 MHz instrument. Whereso characterized, all observed protons are reported as parts-per-million(ppm) downfield from tetramethylsilane (TMS) or other internal referencein the appropriate solvent indicated.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method (commonlyreferred to as an ESI MS) utilizing a PE SCIEX API 150EX MS instrumentinstrument or an Agilent 1100 series LC/MSD system. Compounds having anisotopic atom, such as bromine and the like, are generally reportedaccording to the detected isotopic pattern, as appreciated by thoseskilled in the art.

The compounds disclosed and described herein have been named usingeither (1) the naming convention provided with Chem-Draw Ultra 11.0software, available in Chem Office, or (2) by the ISIS database software(Advanced Chemistry Design Labs or ACD software).

Example 1 Intermediate A

Synthesis of7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amineStep 1:

A RBF was charged with 2,5-dibromobenzoic acid (1244 g, 4.44 mol),5-hydroxy-2-chloropyridine (663.3 g, 5.12 mol) and cesium carbonate(2893.3 g, 8.88 mol). The resulting mixture was stirred for 20 minutesunder nitrogen atmosphere at which time copper (I)trifloromethanesulfonate toluene complex (59.7 g, 0.115 mol), toluene (9L) and EtOAc (39 mL) were added in sequence. The resulting suspensionwas heated to 105° C. for 2 h and cooled to RT. The toluene was decantedand water (8 L) and EtOAc (8 L) were added to the residue. The mixturewas stirred until the solids were completely dissolved. The organiclayer was separated and the pH of the aqueous layer was adjusted to pH2˜3 with 6N HCl. This mixture was then extracted with EtOAc (3×5 L). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to give 1.28 kg of5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid as brown solid, whichwas used in next step without further purification.

Step 2:

A mixture of 5-bromo-2-(6-chloropyridin-3-yloxy)benzoic acid (1.28 kg,4.44 mol), diethylamine (461 mL, 4.44 mol), HOBT (600 g, 4.44 mol),DIPEA (1.547 L, 8.88 mol) in anhydrous DCM (8 L) was cooled to 0° C.EDCI (851.2 g, 4.44 mol) was added to the reaction mixture and it wasstirred at 0° C. for 30 minutes and then at RT overnight. The reactionmixture was sequentially washed with aqueous NaHCO₃, brine and waterbefore being dried over MgSO₄. Filtration and concentrated under reducedpressure provided a residue that was purified by silica gelchromatography (5-20% EtOAc in hexane) to provide 950 g of5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide.

Step 3:

A solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide(457.5 g, 1.23 mol) in THF (3 L) was cooled to 74 to 78° C. and treatedwith a solution of LDA (2M in heptane/THF/ethyl benzene, 2.25 L, 4.5mol. After the addition was complete, the solution was stirred for 30min at 78° C. The cold bath was removed and then the reaction wasquenched with saturated aqueous NH₄Cl (1 L), maintaining the temperaturebelow 10° C. The mixture was added to an addition funnel and the layerswere separated. The aqueous layer was extracted with EtOAc (3×2.5 L).The combined organic layers were dried over sodium sulfate, filtered andpassed through a pad of silica gel. The filtrate was evaporated, and theresidue was triturated with DCM to give 35 g of7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one. The mother liquor wasevaporated and the solid thus obtained was purified by recrystallizationusing dichloromethane/hexanes to give 90 g of7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one.

Step 4:

A 500-mL RBF was charged with7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (12.3789 g, 39.9 mmol),trimethylsulfonium iodide (8.95 g, 43.9 mmol), and DMSO (199 mL). Theresulting slurry was stirred vigorously for 5 minutes leading to a tancolored slurry before potassium 2-methylpropan-2-olate (4.92 g, 43.9mmol) was added in one portion. The resulting reddish orange solutionwas maintained at RT for 2 hours at which time azidotrimethylsilane(10.49 mL, 80 mmol) was added in one portion. The heterogeneous mixturebecame homogeneous after 2-3 hours. The solution was maintained at RTovernight before being diluted with ethyl acetate and transferred to aseparatory funnel containing saturated NaHCO₃ (500 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (3×250 mL). Thecombined organic layers were sequentially washed with water and brinebefore being dried over sodium sulfate, filtered and concentrated invacuo to provide an orange oil that was evaporated from DCM (3×250 mL)to provide5-azido-7-bromo-3-chloro-5-((trimethylsilyloxy)methyl)-5H-chromeno[2,3-c]pyridineas an orange foam that was carried on without further purification. Thederived foam was dissolved in THF (250 mL) and cooled to 0° C. at whichpoint LAH (2M in THF) (39.9 mL, 80 mmol) was added at a fast dropwiserate over 5-10 minutes. The reaction immediately became red upon theaddition of LAH. The reaction was maintained at 0° C. for 2 hours thenallowed to warm to RT for 30 minutes. The reaction was diluted with 150mL of THF and quenched with by the addition of sodium sulfatedecahydrate (38.5 g, 120 mmol), which was added over the course of 5minutes. After the addition was complete the slurry was stirred at RTfor 1.5 hours before being filtered through a pad of celite. The filterpad was washed with THF (5×100 mL, with agitation). The filtrate wasconcentrated under vacuum to give a brown foam. The foam wasconcentrated from DCM twise and left under vacuum overnight. The solidwas taken up in DCM (75 mL) and heated to boiling for 1 minute. Themixture was cooled to RT, and then placed in the refridgerator for 1hour. The resulting solid was filtered, washed with DCM (50 mL), andair-dried under a stream of N₂ (g) for 1 hour to provide(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (8.94g) as a light orange solid.

Step 5:

A 200-mL RBF was charged with(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (5.416g, 15.86 mmol), tetrabutylammonium hydrogen sulfate (0.269 g, 0.793mmol), THF (79 mL), and acrylonitrile (5.22 mL, 79 mmol) to give aclear, brown solution. NaOH (2N aq.) (19.82 mL, 39.6 mmol) was added,and the resulting biphasic mixture was stirred for 4 h. The mixture wasdiluted with water (110 mL) and extracted with EtOAc (3×50 mL). Thecombined organic extracts were washed with water (100 mL), washed withbrine, dried over sodium sulfate, filtered, and concentrated. The crudeproduct was purified by chromatography on silica gel (0-100%EtOAc/Hexane) to afford3-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)propanenitrile.¹H NMR (400 MHz, DMSO-d₆) δ=8.28 (d, J=0.4 Hz, 7H), 7.98 (s, 7H), 7.88(d, J=0.4 Hz, 7H), 7.50 (dd, J=2.5, 8.7 Hz, 8H), 7.13 (d, J=8.7 Hz, 7H),3.61-3.48 (m, 2H), 3.34 (t, J=6.0 Hz, 2H), 2.95 (s, 2H); MS m/z=394.0.Calc'd for C₁₆H₁₄BrClN₃O₂: 394.0.

Step 6:

A 500-mL RBF was charged with3-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)propanenitrile(3.967 g, 10.05 mmol) and toluene (100 mL) to give a clear solution.Trimethylaluminum (10.55 mL of a 2M solution in toluene, 21.11 mmol) wasadded, and the resulting mixture was stirred for 5 min. A refluxcondenser was attached, and the mixture was heated to reflux for 1 h.After the mixture had cooled to RT, a saturated aq. Rochelle's saltsolution (200 mL) was slowly added. The mixture was stirred vigorouslyfor 48 h and was then diluted with EtOAc (200 mL) and water (300 mL).The layers were separated, and the aq. layer was extracted with EtOAc(2×200 mL). The combined organic extracts were washed with water (200mL), washed with brine, dried over sodium sulfate, filtered, andconcentrated. The residue was taken up in DCM/MeOH and filtered to give615 mg of the desired product an off-white solid. The filtrate wasconcentrated, and the residue was purified by chromatography on silicagel (0-10% MeOH/DCM). The product obtained from chromatography wascombined with the above solid to give7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amineas a cream-colored solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.37 (d, J=0.4 Hz,1H), 7.62-7.43 (m, 2H), 7.35 (s, 1H), 7.22 (dd, J=0.5, 8.4 Hz, 1H), 6.27(br. s., 2H), 3.94-3.72 (m, 2H), 3.70-3.47 (m, 2H), 3.05-2.75 (m, 2H).MS m/z=394.0. Calc'd for C₁₆H₁₄BrClN₃O₂: 394.0.

Example 2 Method 1: Using Intermediate A

Synthesis of(E)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amineStep 1:

A vial was charged with(E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine(280.9 mg, 0.712 mmol), 2-fluoropyridin-3-ylboronic acid (150 mg, 1.068mmol), Pd(AmPhos)₂Cl₂ (25.2 mg, 0.036 mmol), and potassium phosphate(453 mg, 2.135 mmol). The vial was flushed with Ar (g), then 1,4-dioxane(2669 μL) and water (890 μL) were added in sequence. The vial was sealedand heated in a microwave reactor for 20 min at 90° C. The mixture wasextracted with EtOAc (3×), and the combined organic extracts wereconcentrated. The crude product was purified by chromatography on silicagel (0-10% MeOH/DCM) to give(E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amineas a white solid.

MS m/z=411.0. Calc'd for C₂₁H₁₇ClFN₄O₂: 411.1.

Step 2:

A vial was charged with(E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine(142 mg, 0.346 mmol), 2-fluoropyridin-4-ylboronic acid (122 mg, 0.864mmol), Pd(AmPhos)₂Cl₂ (12.24 mg, 0.017 mmol), and potassium phosphate(220 mg, 1.037 mmol). The vial was flushed with Ar (g), then dioxane(1296 μL) and water (432 μL) were added in sequence. The vial was sealedand heated in a microwave reactor for 30 min at 110° C. The mixture wasextracted with EtOAc (3×), and the combined organic extracts wereconcentrated. The crude product was purified by chromatography on silicagel (10-100% of a 90:10:1 mixture of DCM/MeOH/NH₄OH in DCM) to give(E)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amineas a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.71 (d, J=0.4 Hz, 1H),8.38 (d, J=5.3 Hz, 1H), 8.26 (td, J=1.5, 4.8 Hz, 1H), 8.13 (ddd, J=1.9,7.5, 10.4 Hz, 1H), 8.07 (s, 1H), 7.95 (td, J=1.8, 5.2 Hz, 1H), 7.72 (s,1H), 7.69-7.59 (m, 2H), 7.50 (ddd, J=1.9, 4.9, 7.4 Hz, 1H), 7.42 (d,J=8.6 Hz, 1H), 6.16 (br. s., 2H), 3.86 (t, J=5.6 Hz, 2H), 3.72 (q,J=12.8 Hz, 2H), 3.09-2.90 (m, 2H). MS m/z=472.0. Calc'd forC₂₆H₂₀F₂N₅O₂: 472.2. The racemic material (104 mg) was subjected tochiral SFC separation, using 35% MeOH with diethylamine to afford 45 mgof the (R)-enantiomer (peak 1) and 44 mg of the (S)-enantiomer (peak 2)as white solids.

Example 3 Intermediate B

Synthesis of(E)-5-amino-7′-bromo-4′-fluoro-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-2′-olStep 1:

A dry 100 L glass jacketed reactor equipped with an addition funnel,reflux condenser, solids addition system and temperature probe wascharged with 2,5-dibromobenzoic acid (2685 g, 9.6 mol) and copper (I)triflate toluene complex (2:1, 50.0 g, 0.2 mol). Toluene (30 L) andEtOAc (20 mL) were then charged, followed by 2-methoxy-4-fluorophenol(1500 g, 10.6 mol). With vigorous stirring cesium carbonate (6258 g,19.2 mol) was added in portions. The mixture was heated to 90° C. for 4hours. The mixture was cooled to 35° C. and water (15 L) was added.After 15 minutes of stirring the phases were sping and the aqueous phasewas washed with toluene (7.5 L). With stirring, EtOAc (15.0 L) was addedto the rich aqueous phase, followed by 6 M HCl (5.6 L) keeping theinternal temperature below 30° C. The layers were separated and theorganic layers were dried over magnesium sulfate, filtered through a padof celite and concentration to provide a solid that was re-slurried in915 mL of EtOAc and 9.2 L of heptanes. Stirring was continued for 1 hourbefore the solids were filtered and washed with heptanes. The resultingsolids were dired to provide 2560 g of5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a cream coloredsolid.

Step 2:

A dry 100 L glass jacketed reactor equipped with an addition funnel,reflux condenser and temperature probe was charged with5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid (2340 g, 6.9 mol). TFA(11.7 L) was carefully added to the solution followed by TFAA (1144 mL).Boron trifluoride diethyl etherate (85 mL, 0.68 mol) was then carefullyadded to the reaction mixture. The mixture was stirred for 4 hours atwhich point the reaction was transferred to another 100 L glass reactorcontaining 35.1 L of water cooled to 0° C. The resulting slurry wasallowed to warm to RT and stir for 1 hour. The solids were filtered andwashed with water (4.7 L) and 3 N NaOH (2×3.5 L) and water (7 L). Thesolids were transferred into a 22 L reactor and acetone (4.7 L) wasadded. The solids were slurried for 1.5 hour and the filtered, washingwell with acetone (4.7 L). An additional slurry with acetone (6.4 L@ 45°C.) provided 1310 g of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one as anoff white solid.

Step 3:

To a suspension of 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (25.00 g,77 mmol) and trimethylsulfonium iodide (23.68 g, 116 mmol) in DMSO (130mL) and THF (130 mL) in 1 L RB flask was added potassium tert-butoxide(1M in THF) (116 mL, 116 mmol) dropwise over 10 minutes. Stirring wascontinued for 15 min at room temperature at which point trimethylsilylazide (20.54 mL, 155 mmol) was added. The mixture was stirred foradditional 40 minutes and then the reaction was quenched by addition of100 ml of saturated aqueous sodium bicarbonate. After stirring for 10minutes ethyl acetate (100 ml) and water (100 ml were added and thelayers were split. The organic layer was washed with water (3×100 ml)and brine (100 ml), then dried with MgSO₄, concentrated and dried invacuo. The yellow residue was redissolved in 250 ml THF and cooled in anice-water bath. Lithium aluminum hydride (1 M in THF) (108 mL, 108 mmol)was added dropwise and the mixture was stirred for 5 minutes at 0° C.before the bath was removed and the mixture was allowed to warm up toroom temperature. The flask was re-cooled again in ice-water bath andsodium sulfate decahydrate (21.98 g, 155 mmol) was added in portions (becareful as there is rapid evolution of gas). The mixture was stirred for5 minutes in the ice bath, and then the bath was removed. After dilutionwith 100 ml EtOAc, the gelatinous mixture was filtered through the padof Celite and filter cake was washed with EtOAc (100 ml). The filtratewas concentrated and dried in vacuo. The yellow foam was redissolved in60 ml DCM and a white solid crystallized immediately. The solid wasfiltered, washed with DCM (2×10 ml) and dried on air for 1 hr to afforda portion of desired product. The filtrate was concentrated under astream of N₂ gas to ˜¼ of the volume and the precipitated solid wasfiltered, washed quickly with DCM and dried on air to afford additional(9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methanol.

Step 4:

A 100-mL RBF was charged with(9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methanol (2.318 g,6.54 mmol), tetrabutylammonium hydrogen sulfate (0.111 g, 0.327 mmol),THF (32.7 mL), and acrylonitrile (2.154 mL, 32.7 mmol) to give a clearsolution. NaOH (8.18 mL of a 2N aq. solution, 16.36 mmol) was added, andthe resulting mixture was stirred for 1.5 h. The reaction mixture wasdiluted with EtOAc (70 mL), washed with water (2×50 mL), washed withbrine, dried over sodium sulfate, filtered, and concentrated in vacuo.The crude product was purified by chromatography on silica gel (0-10%MeOH/DCM) to give3-((9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methoxy)propanenitrileas a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.97 (d, J=2.4 Hz, 1H),7.45 (dd, J=2.5, 8.7 Hz, 1H), 7.19 (dd, J=1.7, 2.9 Hz, 1H), 7.09 (d,J=8.6 Hz, 1H), 6.96-6.89 (m, 1H), 3.77 (s, 3H), 3.64 (t, J=6.0 Hz, 1H),3.54-3.42 (m, J=2.1 Hz, 3H), 3.38-3.23 (m, 2H), 2.85-2.74 (m, 2H).

Step 5:

A 250-mL round-bottom flask was charged with3-((9-amino-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)methoxy)propanenitrile(2.78 g, 6.83 mmol) and toluene (45.5 mL) to give a pale-green solution.Trimethylaluminum (7.17 mL of a 2M solution in toluene, 14.34 mmol) wasadded, and a reflux condenser was attached. After stirring for 1 min,the flask was heated to 90° C. for 1 h. After this time, the mixture wascooled to RT. Sodium sulfate decahydrate (3.4 g) was added slowly over 5min, and the mixture was stirred overnight. In the morning, the mixturewas diluted with EtOAc (50 mL) and filtered through celite. The filterpad was washed with EtOAc (3×50 mL). The combined filtrates wereconcentrated to give a pale-yellow solid. The crude product was purifiedby chromatography on silica gel (0-10% MeOH/DCM) to give(E)-7′-bromo-4′-fluoro-2′-methoxy-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amineas a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.53 (d, J=2.4 Hz, 1H),7.47 (dd, J=2.5, 8.6 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.95 (dd, J=2.9,12.3 Hz, 1H), 6.69 (dd, J=1.5, 2.9 Hz, 1H), 6.15 (br. s., 2H), 3.83-3.69(m, 5H), 3.64-3.45 (m, 2H), 3.00-2.74 (m, 2H). MS m/z=411.0. Calc'd forC₁₈H₁₇BrFN₂O₃: 407.1.

Step 6:

A solution of(E)-7′-bromo-4′-fluoro-2′-methoxy-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine(0.990 g, 2.431 mmol) in DCM (24.31 mL) was cooled in an ice-bath for 5min. Boron tribromide (0.919 mL, 9.72 mmol) was added dropwise to give aresulting brown mixture. The mixture was stirred for 1 h, at which timea saturated aq. sodium bicarbonate solution (25 mL) was added. Themixture was stirred for 5 min. and concentrated on a rotary evaporatorto remove the DCM. The mixture was heated with a heat gun for 5 min, andat this point the solid was scraped from the sides of the flask. Theflask was sonicated for 1 min, then reheated for 2 min. The flask wasagain sonicated for 1 min, then cooled to RT. The solid was filtered.The filter cake was washed twice with water, then air-dried under astream of N₂ (g) for 1.5 h to give(E)-5-amino-7′-bromo-4′-fluoro-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-2′-olas a light-yellow solid. The solid was used without furtherpurification.

MS m/z=393.0. Calc'd for C₁₇H₁₅BrFN₂O₃: 393.0.

Example 4 Method 2: Using Intermediate B

Synthesis of(E)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amineStep 1:

A vial was charged with(E)-5-amino-7′-bromo-4′-fluoro-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-2′-ol(222.7 mg, 0.566 mmol), cesium carbonate (738 mg, 2.265 mmol), and DMF(2832 μL) to give a yellow suspension. The resulting mixture was stirredfor 10 min, then neopentyl iodide (225 μL, 1.699 mmol) was added. Thevial was capped and heated to 100° C. for 2 h. The mixture was dilutedwith water and extracted with EtOAc (3×). The combined organic extractswere dried over sodium sulfate, filtered, and concentrated. The crudeproduct was purified by chromatography on silica gel (0-10% MeOH/DCM) togive(E)-7′-bromo-4′-fluoro-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amineas a yellow oil.

MS m/z=463.0. Calc'd for C₂₂H₂₅BrFN₂O₃: 463.1.

Step 2:

A vial was charged with(E)-7′-bromo-4′-fluoro-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine(158 mg, 0.341 mmol), 2-fluoropyridin-3-ylboronic acid (96 mg, 0.682mmol), potassium phosphate (217 mg, 1.023 mmol), and AmPhos (12.07 mg,0.017 mmol) were added. The vial was flushed with Ar (g), then1,4-dioxane (1279 μL) and water (426 μL) were added in sequence. Thevial was heated to 90° for 45 min. The mixture was cooled to RT andextracted with EtOAc (3×). The combined organic extracts wereconcentrated, and the crude product was purified by chromatography onsilica gel (10-100% of a 90:10:1 mixture of DCM/MeOH/NH₄OH in DCM) togive(E)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amineas a light-yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=8.24 (td, J=1.5,4.8 Hz, 1H), 8.10 (ddd, J=1.9, 7.5, 10.4 Hz, 1H), 7.64-7.53 (m, 2H),7.49 (ddd, J=1.9, 5.0, 7.3 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 6.95 (dd,J=2.7, 12.4 Hz, 1H), 6.81 (dd, J=1.4, 2.7 Hz, 1H), 6.11 (br. s., 2H),3.84-3.69 (m, J=4.2 Hz, 2H), 3.67-3.54 (m, 4H), 2.98-2.75 (m, 2H),1.06-0.95 (m, 9H). MS m/z=480.2. Calc'd for C₂₇H₂₈F₂N₃O₃: 480.2. Thepurified racemates (58 mg) were separated using a chiral SFC column,eluting with 55% MeOH with diethylamine, to afford (S)-enantiomer(peak 1) and (R)-enantiomer (peak 2) as white solids.

Example 5 Intermediate C

Synthesis of(E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine(Example 3A) Steps 1-3:

Steps 1-3 were carried out in accordance with that described in Example1, Steps 1-3 hereinabove, to provide 90 g of7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one.

Step 4:

A mixture of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one (5.0 g,48.3 mmol), (R)-2-methylpropane-2-sulfinamide (5.85 g, 48.3 mmol), andtetraethoxytitanium (10.00 mL, 48.3 mmol) in dry THF (100 mL) was heatedat 75° C. for 24 hours. The solution was cooled to RT and slowly pouredinto a 2 L flask containing 0.35 L of brine and 0.35 L of saturatedsodium bicarbonate. The resulting mixture was stirred vigorously for 15minutes before being filtered through a pad of celite. The pad waswashed with EtOAc. The filtrate was poured into a separatory funnel andthe aqueous layer was extracted with EtOAc (2×500 mL). The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated in vacuo to provide an orange solid. Thissolid was purified by silica gel chromatography using 0-15% Hexane/EtOACto provide(R,E)-N-(7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamideas an orange solid. M+H=415.0@2.90 min.

Step 5:

To a solution of(S,Z)—N-(7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide(3000 mg, 7.25 mmol) in THF (25 mL) was slowly added2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in diethyl ether, 36.3 mL,18.13 mmol) in an ice bath. The mixture was stirred at 0° C. for 25mins, then 80 mL of saturated NH₄Cl aqueous solution was added to quenchthe reaction. The reaction mixture was extracted with EtOAc (2×35 mL).The organic extract was washed with saturated NaCl aqueous solution,dried over MgSO4, filtered and concentrated to give the crude materialas an orange solid. The crude material was absorbed onto a plug ofsilica gel and purified by chromatography through a Redi-Sep pre-packedsilica gel column (80 g), eluting with a gradient of 0% to 20% to 50%DCM/MeOH (90/10) in DCM. The fractions which contain mixture wererepurified using 40 g Redi-Sep pre-packed silica gel column and elutingwith a gradient of 0% to 20% to 50% DCM/MeOH (90/10) in DCM. The desiredfractions were collected and concentrated to provide tert-butyl2-((S)-7-bromo-3-chloro-5-((S)-1,1-dimethylethylsulfinamido)-5H-chromeno[2,3-c]pyridin-5-yl)acetate(isomer A, high Rf), and tert-butyl2-((R)-7-bromo-3-chloro-5-((S)-1,1-dimethylethylsulfinamido)-5H-chromeno[2,3-c]pyridin-5-yl)acetate(isomer B, low Rf) as off-white solid. Isomer A: ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.97 (s, 9H) 1.03 (s, 9H) 3.42 (s, 2H) 6.41 (s, 1H) 7.15(d, J=8.71 Hz, 1H) 7.52 (dd, J=8.80, 2.35 Hz, 1H) 7.79 (s, 1H) 7.98 (d,J=2.45 Hz, 1H) 8.37 (s, 1H). Isomer B: ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.97 (s, 9H) 1.04 (s, 9H) 3.34 (s, 1H) 3.42 (s, 1H) 6.35 (s, 1H) 7.16(d, J=8.80 Hz, 1H) 7.54 (dd, J=8.80, 2.45 Hz, 1H) 7.77 (d, J=2.35 Hz,1H) 7.95 (s, 1H) 8.35 (s, 1H).

Step 6:

A solution of tert-butyl2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-5H-chromeno[2,3-c]pyridin-5-yl)acetate(isomer A) (720 mg, 1.359 mmol) in dry THF (5.5 mL) was brought to −78°C. and diisobutylaluminum hydride (5.44 mL, 5.44 mmol) was added slowly.The mixture was brought to 0° C. after diisobutylaluminum hydrideaddition, and stirred at this temperature for 0.5 hr. The reactionmixture was quenched with saturated Rochelle's salt (˜40 mL) and stirredat RT for overnight. The organic layer was separated and the aqueousphase was extracted by EtOAc. The combined organics were washed withsaturated NaCl aqueous solution, dried over MgSO₄, filtered, andconcentrated to affordN-(7-bromo-3-chloro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamideas off-white solid that was advanced without further purification.

Step 7:

A 100 mL RBF was charged withN-(7-bromo-3-chloro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide(625 mg, 1.359 mmol), tetrabutylammonium hydrogen sulfate (138 mg, 0.408mmol), THF (6.80 mL), and bromoacetonitrile (0.852 mL, 12.23 mmol) togive a cloudy, light brown solution. The resulting solution was stirredvigorously for 5 min. Then a 2N aq. solution of sodium hydroxide (13.600mL, 27.2 mmol) was added in one portion. The solution changed into darkbrown color. 3 Hrs later, LCMS showed an incomplete conversion (SM:product=1:1.5). 1 additional molar equivalent of BrCH2CN was added, andthe mixture was stirred for 1 hr. The reaction mixture was diluted withwater and extracted with EtOAc. The organic extract was washed withsaturated NaCl aqueous solution, dried over MgSO4, filtered andconcentrated to give the crude material as a brown solid. The crudematerial was absorbed onto a plug of silica gel and purified bychromatography through a Redi-Sep pre-packed silica gel column (12 g),eluting with a gradient of 25 to 40 to 80% DCM/MeOH/NH4OH (90:10:1) in40% EtOAc in heptane to yieldN-(7-bromo-3-chloro-5-(2-(cyanomethoxy)ethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamideas off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.12 (m, 9H)2.59 (d, J=9.49 Hz, 2H) 3.03 (s, 2H) 4.10 (s, 2H) 6.52 (s, 1H) 7.10-7.20(m, 1H) 7.51-7.59 (m, 1H) 7.72-7.80 (m, 1H) 7.93 (d, J=2.45 Hz, 1H)8.33-8.40 (m, 1H).

Step 8:

To a vial was addedN-(7-bromo-3-chloro-5-(2-(cyanomethoxy)ethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide(242 mg, 0.485 mmol) and HCl (4.0M solution in 1,4-dioxane, 0.970 mL,3.88 mmol) in dioxane (4 mL). The mixture was stirred at RT for 20 mins,then quenched with 5 mL of a saturated aqueous solution of Na₂CO₃ andextracted into EtOAc. The organic extract was washed with saturated NaClaqueous solution, dried over MgSO₄, filtered and concentrated to givethe crude product as orange oil. The crude product was dissolved with 4mL of toluene and trimethylaluminum solution (2M in toluene, 0.728 mL,1.455 mmol) was added to the mixture (exothermic after addition). Themixture was heated to 90° C. in oil bath for 10 min, then quenched withRochelle's salt (12 mL) at 0° C. and stirred overnight at RT. Thereaction mixture was diluted with water and extracted with EtOAc (10mL×2). The organic extract was washed with saturated NaCl aqueoussolution, dried over MgSO₄, filtered and concentrated to give the crudematerial as orange oil. It was absorbed onto a plug of silica gel andpurified by chromatography through a gold Redi-Sep pre-packed silica gelcolumn (12 g), eluting with a gradient of 30% to 50% to 80%DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane to provide(E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amineas off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.03-2.22 (m, 4H)4.42 (s, 2H) 6.18 (br. s., 2H) 7.21 (d, J=8.51 Hz, 1H) 7.39 (s, 1H)7.45-7.62 (m, 2H) 8.36 (s, 1H). The other stereoisomer is Example 3B inTable 1.

Example 6 Method 1: Using Intermediate C

Synthesis of(R,E)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amineStep 1:

To a vial was added(E)-7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine(80 mg, 0.203 mmol), potassium phosphate (129 mg, 0.608 mmol),2-fluoropyridin-3-ylboronic acid (30.0 mg, 0.213 mmol),1,1-bis[(di-t-butyl-p-dimethylaminophenyl]palladium(ii) chloride (7.18mg, 10.14 μmol), dioxane (1014 μL), water (338 μL). The resultingmixture was purged with N₂ gas and heated at 90° C. in microwave reactorfor 25 mins. It was diluted with water and extracted into EtOAc. Theorganic extract was washed with saturated NaCl aqueous solution, driedover MgSO₄, filtered and concentrated to give the crude material as aorange solid. The crude material was absorbed onto a plug of silica geland purified by chromatography through a gold Redi-Sep pre-packed silicagel column (12 g), eluting with a gradient of 50% to 80% DCM/MeOH/NH4OH(90/10/1) in 40% EtOAc in Heptane, to provide(E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amineas off-white solid.

Step 2:

To a vial was added(E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine(50 mg, 0.122 mmol), potassium phosphate (78 mg, 0.365 mmol),2-fluoropyridin-4-ylboronic acid (34.3 mg, 0.243 mmol), and1,1-bis[(di-t-butyl-p-dimethylaminophenyl]palladium(ii) chloride (4.31mg, 6.09 μmol), dioxane (609 μL) and water (203 μL). The reactionmixture was purged with N₂ gas and heated at 100° C. in microwavereactor for 15 mins. It was diluted with water and extracted with EtOAc.The organic extract was washed with saturated NaCl aqueous solution,dried over MgSO₄, filtered and concentrated in vacuo to give the crudematerial. The crude was absorbed onto a plug of silica gel and purifiedby chromatography through a Redi-Sep pre-packed silica gel column (12g), eluting with a gradient of 25% to 40% to 80% DCM/MeOH (90/10) inDCM, to provide(R,E)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amineas off-white solid. MS m/z=472.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.01-2.14 (m, 1H) 2.24-2.41 (m, 1H) 3.39 (dt, J=11.25, 5.62 Hz, 2H)4.37-4.47 (m, 1H) 4.47-4.61 (m, 1H) 6.13 (br. s., 2H) 7.41 (d, J=8.31Hz, 1H) 7.50 (ddd, J=7.26, 5.01, 1.91 Hz, 1H) 7.60 (dt, J=8.39, 1.87 Hz,1H) 7.67-7.75 (m, 2H) 7.89-7.95 (m, 1H) 8.03-8.16 (m, 2H) 8.25 (dt,J=4.82, 1.50 Hz, 1H) 8.38 (d, J=5.28 Hz, 1H) 8.66-8.77 (m, 1H).

Example 7 Method 3: Using Intermediate C—(S)-enantiomer

Synthesis of(S)-3-(3,3-difluoropyrrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amineStep 1:

The first step was run in accordance with that described above inExample 6, Step 1 to afford the same product. Yield: 43.1%. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.06-2.15 (m, 1H) 2.15-2.25 (m, 1H) 3.22-3.40 (m,2H) 4.33-4.51 (m, 2H) 6.13 (br. s., 2H) 7.37 (d, J=8.41 Hz, 1H) 7.44 (s,1H) 7.49 (ddd, J=7.24, 4.99, 1.86 Hz, 1H) 7.58 (dt, J=8.44, 1.90 Hz, 1H)7.64 (s, 1H) 8.01-8.11 (m, 1H) 8.20-8.29 (m, 1H) 8.39 (s, 1H).

Step 2:

A vial was charged with(S)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine(50.0 mg, 0.122 mmol), 3,3-difluoropyrrolidine hydrochloride (36.0 mg,0.243 mmol), and RuPhos precatalyst (8.87 mg, 0.012 mmol). The vial wasflushed with N₂ gas, then lithium bis(trimethylsilyl)amide (1M in THF)(608 μl, 0.608 mmol) was added slowly to the mixture. After about 10mins, the mixture was diluted with saturated aqueous ammonium chlorideand extracted with EtOAc. The combined organic extracts were dried overMgSO₄, filtered, and concentrated. The residue was purified on a 12 gRedi-Sep Gold silica-gel column eluting with a 90:10:1 mixture ofDCM/MeOH/NH₄OH in EtOAc to provide(S)-3-(3,3-difluoropyrrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine as off white solid. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.06 (br. s., 1H) 2.14 (br. s., 1H) 2.51-2.61(m, 2H) 3.33-3.41 (m, 2H) 3.58 (t, J=7.59 Hz, 2H) 3.81 (t, J=13.04 Hz,2H) 4.34-4.46 (m, 2H) 6.00 (br. s., 2H) 6.57 (s, 1H) 7.28 (d, J=8.33 Hz,1H) 7.48 (t, J=5.34 Hz, 1H) 7.53 (d, J=8.76 Hz, 1H) 7.62 (s, 1H)8.00-8.07 (m, 1H) 8.10 (s, 1H) 8.22 (d, J=4.06 Hz, 1H).

Example 8

Synthesis of 2-Bromo-7-methoxy-9H-xanthen-9-one Step 1:2-(4-Bromophenoxy)-5-methoxybenzoic acid

4-Bromophenol (8.7 g, 50 mmol), Cs₂CO₃ (16 g, 50 mmol), CuOTf toluenecomplex (2:1) (0.625 mmol, 5 mol % Cu, 150 mg), ethyl acetate (0.25 ml,2.5 mmol) were added to a solution of 2-bromo-5-methoxybenzoic acid(11.6 g, 50 mmol) in toluene (40 mL) in a sealed tube. The reactionmixture was purged with N₂, and was heated to 110° C. until the arylhalide was consumed as determined by LC-MS (48 h). After cooling to RT,the mixture was filtered through a Celite plug. The Celite plug waswashed with EtOAc. The mixture was acidified by 1N HCl, and extracted w/EtOAc. The combined organic phases were washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated. This residue waspurified via column chromatography on silica gel (gradient elution with0-10% MeOH/DCM) to afford 2-(4-bromophenoxy)-5-methoxybenzoic acid. MSm/z=324.9 [M+H]⁺. Calc'd for C₁₄H₁₁BrO₄: 323.1.

Step 2: 2-Bromo-7-methoxy-9H-xanthen-9-one

Sulfuric acid (41 ml, 765 mmol) was added to2-(4-bromophenoxy)-5-methoxybenzoic acid (3750 mg, 12 mmol) at RT. Thereaction mixture was stirred at 60° C. for 60 min. LCMS showed completereaction. The reaction mixture was cooled to RT and poured slowly overstirred mixture of ice and water (100 ml). The tan precipitate wasfiltered and washed with water (3×30 ml), twice with 30 ml of 0.5N NaOH,and with water again. The residue was recrystallized from 40 ml THF togive the title compound. MS m/z=307.2 [M+H]⁺. Calc'd for C₁₄H₉BrO₃:305.1.

Example 9

Synthesis of 7-Bromo-3-fluoro-2-methoxy-9H-xanthen-9-one

The titled compound was prepared using 2-bromo-4-fluoro-5-methoxybenzoicacid as the starting material, which starting material was prepared asfollows:

Step 1: 4-Bromo-2-fluoro-5-methylphenol

2-fluoro-5-methylphenol (23.8 g, 0.19 mol) and bromine (9.7 ml, 0.19mol) are combined in 50 ml of glacial acetic acid and stirred at RT forone hour. Acetic acid was removed under vacuum. The liquid was dilutedwith ethyl acetate and washed with water. The organic layer was washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated to afford 4-bromo-2-fluoro-5-methylphenol (38 g, 98% yield)as a colorless liquid. No [M+H] peak by LCMS. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.98 (s, 1H) 2.22 (s, 3H) 6.81 (dd, J=9.15, 0.54 Hz,1H) 7.17 (d, J=9.88 Hz, 1H)

Step 2: 1-Bromo-5-fluoro-4-methoxy-2-methylbenzene

4-Bromo-2-fluoro-5-methylphenol (40 g, 0.19 mol), cesium carbonate (75g, 0.23 mol), and iodomethane (15 ml, 0.23 mol) were combined in 100 mlof DMF and stirred at RT for one hour (exothermic). The solution wasdiluted with ethyl acetate and filtered. The solution was washed withwater twice, dried with anhydrous sodium sulfate, filtered, andconcentrated. The product was purified via silica gel columnchromatography (RediSep 330 g column) using 0-50% ethyl acetate inhexane to afford 1-bromo-5-fluoro-4-methoxy-2-methylbenzene (38 g, 89%yield) as a colorless liquid. No [M+H] peak by LCMS. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 2.24 (s, 3H) 3.76 (s, 3H) 6.73 (d, J=8.80 Hz, 1H)7.13 (d, J=10.56 Hz, 1H)

Step 3: 2-Bromo-4-fluoro-5-methoxybenzoic acid

Potassium permanganate (53 g, 3.4 mol) was added to a solution of1-bromo-5-fluoro-4-methoxy-2-methylbenzene (37 g, 1.7 mol) in 75 ml ofpyridine and 150 ml of water at 60° C. The solution was stirred at 60°C. degrees for 24 hours. The solution was filtered and the solids werewashed with a solution of water/methanol (50:50). The filtrate wasconcentrated to approximately 100 ml, then acidified (pH 1) withconcentrated HCl. The solid was collected by filtration and dried undervacuum to afford 2-bromo-4-fluoro-5-methoxybenzoic acid as an off whitesolid. MS m/z=248.9 [M+H].

Step 4: 7-Bromo-2-fluoro-3-methoxy-9H-xanthen-9-one

Sulfuric acid (41 ml, 765 mmol) was added to2-bromo-4-fluoro-5-methoxybenzoic acid (3.75 g, 12 mmol) at RT. Thereaction mixture was stirred at 60° C. for 60 min. LCMS showed completereaction. The reaction mixture was cooled to RT and poured slowly overstirred mixture of ice and water (100 ml). The tan precipitate wasfiltered and washed with water (3×30 ml), twice with 30 ml of 0.5N NaOH,and with water again. The residue was recrystallized from 40 ml THF togive the title compound. MS m/z=326.2 [M+H]⁺. Calc'd for C₁₄H₉BrO₃:325.1.

Example 10

Synthesis of 8-bromo-2-chloro-10H-chromeno[3,2-b]pyridin-10-one Step 1:

A RBF was charged with 3-chloro-2-cyanopyridine (40 g, 289 mmol),4-bromophenol (49.9 g, 289 mmol) and cesium carbonate (113 g, 346 mmol).The reactants were suspended in 50 mL of DMSO and allowed to stir at 85C overnight. The reaction was cooled to RT and 600 mL of water was addedto it. The reaction was filtered and the solid washed with water, thenair dried to provide 3-(4-bromophenoxy)-picolinonitrile as a tan solid.

Step 2:

A mixture of 3-(4-bromophenoxy)-picolinonitrile (57 g, 207 mmol) and 300g of PPA was stirred at 190° C. for 2 h, followed by 180° C. overnight.After cooling to RT, the reaction mixture was poured into 500 g of icewater. After the PH was adjusted to 7 with KOH, the suspension wasfiltered. The solid was washed with large excess of water, followed bywashing with methanol and acetone. The resulting solid was air dried togive 8-bromo-10H-chromeno[3,2-b]pyridin-10-one as a tan solid with >90%purity. The material was carried on to the next step.

Step 3:

To a solution of 8-bromo-10H-chromeno[3,2-b]pyridin-10-one (60 g, 217mmol) and urea peroxide (42.9 g, 456 mmol) in 120 mL of DCM at 0° C. wasadded dropwise trifluoroacetic anhydride (63.9 mL, 456 mmol). Theresulting reaction was stirred for 2 h. The reaction was quenched with10% Na₂S₂O₃, extracted with DCM, dried over Na₂SO₄ and evaporated todryness to give crude 8-bromo-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxideas a pale yellow solid.

Step 4:

To a suspension of 8-bromo-10-oxo-10H-chromeno[3,2-b]pyridine 1-oxide in100 mL of toluene at 0° C. was added dropwise phosphorus oxychloride(35.8 mL, 391 mmol) followed by 2 mL of DMF and the mixture was stiffedat RT overnight. The solvent was evaporated under vacuum and the residuewhich crashed out of water, was filtered and washed with water, methanoland acetone in sequence. The solid was air dried to give8-bromo-2-chloro-10H-chromeno[3,2-b]pyridin-10-one as a tan solid.

Example 11

Synthesis of 7-Bromo-3-methoxy-5H-chromeno[2,3-b]pyridin-5-one Step 1:

A three neck 3-L RBF equipped with an overhead stiffed was charged with6-fluoropyridin-3-ylboronic acid (105 g, 745 mmol) and 1 L of THF. Themixture was cooled to 0° C. and NaOH 6N (373 mL, 2235 mmol) was added.To the resulting mixture was added hydrogen peroxide 30% (126 mL, 4098mmol), dropwise via an addition funnel over the course of 30 minutes.After stirring at 0° C. for 2 hours the mixture was removed from the icebath and maintained at RT for 30 minutes. The reaction was acidified topH 7 with 6 N HCl (ca. 300 mL) and diluted with 500 mL of ether. Theaqueous layer was extracted with ether (2×1 L) and the combined organiclayers were washed with water (1.5 L) then brine before being dried oversodium sulfate. Filtration and concentration provided a white solid thatwas dried on high vac overnight to provide 6-fluoropyridin-3-ol.

Step 2:

To a solution of 6-fluoropyridin-3-ol (75 g, 663 mmol) in DMF (265 mL,663 mmol) were added potassium carbonate (59.7 g, 995 mmol) andiodomethane (108 g, 763 mmol). The resulting slurry was heated at 100°C. for 3 hours. The reaction was diluted with water (1000 mL) and pouredinto a separatory funnel containing diethyl ether (1000 mL). The layerswere separated and the aqueous layer was extracted with diethyl ether(4×500 mL). The combined organic layers were washed with water and thenbrine, dried over sodium sulfate, filtered and concentrated in vacuo toprovide a yellow oil. This oil was diluted with 500 mL of DCM andconcentrated to provide a yellow oil with a large amount of an off whiteprecipitate. The mixture was filtered and the derived solid was washedwell with DCM. The filtrate was concentrate to provide a mixtureconsisting of a yellow oil and an off white solid. The solid wasfiltered, washing with DCM. Repeat this procedure again and thenconcentrated the filtrate to provide a yellow oil. The oil was taken upin 100 mL of ether and flashed through a plug of silica gel with 10:1hexanes:ether to provide 2-fluoro-5-methoxypyridine as a yellow oil.

Step 3:

To a solution of DIPA (54.0 mL, 385 mmol) in THF (1101 mL, 385 mmol) at−60° C. was added BuLi, 2.5 M in hexanes (154 mL, 385 mmol) over 5minutes such that the internal temperature was maintained below −60° C.After stirring for 45 minutes at −65° C. a solution of2-fluoro-5-methoxypyridine (49 g, 385 mmol) in 200 mL of THF was addedover the course of 2 minutes maintaining an internal temperature <−65°C. The reaction was stirred at −70° C. for 1.5 hours then reaction waspoured into a 3 L flask containing 1200 g of crushed dry ice. Thereaction was allowed to warm to 0° C. and then poured into 1000 mL ofwater. The organics were removed under reduced pressure and the aqueouslayer was acidified with 1100 mL of 2 N HCl. The resulting thick whiteslurry was stirred for 1 hour then filtered to provide2-fluoro-5-methoxynicotinic acid as a white solid.

Step 4:

To a slurry of sodium hydride (60% dispersion) (21.74 g, 543 mmol) inDMF (351 mL, 175 mmol) at 0° C. was added 4-bromophenol (60.7 g, 351mmol) over the course of 5 minutes. Stirred at 0° C. for two minutesthen removed from the ice bath and stirred for an additional 5 minutesat room temperature. Added 2-fluoro-5-methoxynicotinic acid (30 g, 175mmol) portionwise over 10 minutes and heated the resulting slurry at140° C. After cooling to RT the mixture was then poured onto 1 kg of iceand was quenched with acetic acid (50.2 mL, 877 mmol) and then 75 mL of6 N HCl. Stirred vigorously for 1 hour, leading to the formation of ared slurry containing a very fine white precipitate. The slurry wasfiltered to provide 2-(4-bromophenoxy)-5-methoxynicotinic acid.

Step 5:

A 2 L RBF charged with polyphosphoric acid (115% H₃PO₄) (300 g, 89 mmol)was heated to 140° C. at which point2-(4-bromophenoxy)-5-methoxynicotinic acid (29 g, 89 mmol) wasintroduced. The thick viscous mixture is slowly stirred while heating at140° C. After heating for 2.5 hours the solution was cooled to 100° C.and then poured onto 1 kg of ice, leading to the formation of a yellowtaffy mixture. The slurry was vigorously stirred for 1 hour leading tothe formation of a fine white precipitate. Filtration of this mixtureproceeded slowly to provide an off white solid. This solid was washedwell with DCM. The filtrate, which contained the desired product, waswashed with brine and concentrated to provide7-bromo-3-methoxy-5H-chromeno[2,3-b]pyridin-5-one as an off-white solid.

Example 12

Synthesis of 7-Bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-oneStep 1:

A 500 mL RBF was charged with 2-fluoro-3-hydroxypyridine (3487 mg, 30.8mmol), 2,5-dibromobenzoic acid (8630 mg, 30.8 mmol), copper (I)trifluoromethane-sulfonate toluene complex (2:1) (399 mg, 0.771 mmol)and cesium carbonate (2.01E+04 mg, 61.7 mmol). To this was added 100 mLof toluene and the mixture was azeotroped to remove about 20 mL oftoluene under reduced pressure. Reaction mixture was then flushed withN2 and was heated to 120° C. for 2 hours. LC-MS analysis showedformation of the desired product along wth significant impurities. Thereaction mixture was cooled to RT and concentrated to give a gummyresidue. The residue was taken up in ethyl acetate (100 mL) and water(75 mL). The aqueous layer was neutralized with 1N HCl to pH ˜2.0-3.0.The aqueous layer was extracted with ethyl acetate (2×150 mL),separated, dried over anhydrous sodium sulfate, and concentrated toyield the crude product as a brown solid which was used directly in thenext step.

Step 2:

A mixture of crude 5-bromo-2-(2-fluoropyridin-3-yloxy)benzoic acid (8.00g, 25.6 mmol), diethylamine (6.63 mL, 64.1 mmol) and TBTU (8.23 g, 25.6mmol) in 8 mL of DMF was stirred overnight. The reaction was quenchedwith Sat. NaHCO3, extracted with EA/H=2:1, washed with brine, dried overNa2 SO4, filtered and evaporated to dryness. CC (DCM to DCM/EA 100:5 to100:10 to 100:20 to 3:1) gave5-bromo-N,N-diethyl-2-(2-fluoropyridin-3-yloxy)benzamide as a yellowsolid.

Step 3:

To a solution of5-bromo-N,N-diethyl-2-(2-fluoropyridin-3-yloxy)benzamide (1.4 g, 3.81mmol) and urea peroxide (1.076 g, 11.44 mmol) in 10 mL of DCM at 0 C wasadded dropwise trifluoroacetic anhydride (1.601 mL, 11.44 mmol) and theresulting reaction was stirred overnight. LCMS showed only less than 50%of desired conversion. The mixture was evaporated to dryness, quenchedwith Sat. NaHCO₃, extracted with EA, dried over Na₂SO₄, filtered andevaporated to dryness. CC (DCM to DCM/EA=3:1 to DCM/MeOH=100:2 to 100:5to 100:10) gave 3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine1-oxide as an offwhite solid.

Step 4:

To a solution of3-(4-bromo-2-(diethylcarbamoyl)phenoxy)-2-fluoropyridine 1-oxide (420mg, 1.096 mmol) in 15 mL of DCM was added dropwise phosphorusoxychloride (301 μL, 3.29 mmol) followed by 2 drops of DMF. Afterstirring at rt for 1 h, the reaction was quenched with sat. NaHCO₃,extracted into EtOAc, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude was purified by column chromatography (DCMto DCM/EtOAc gradient beginning from 10:1 to 5:1 to 3:1) gave5-bromo-2-(6-chloro-2-fluoropyridin-3-yloxy)-N,N-diethylbenzamide as acolorless gum.

Step 5:

To a solution of5-bromo-2-(6-chloro-2-fluoropyridin-3-yloxy)-N,N-diethylbenzamide (120mg, 0.299 mmol) in 5 mL of dry THF at 78° C. was added dropwise lithiumdiisopropylamide, 2.0 m heptane/tetrahydrofuran/ethylbenzene (158 μL,1.195 mmol) (0.6 mL of 2M solution) and the reaction was stirred at −78°C. for 3 h. The reaction was quenched at −78° C. with sat. NH₄Cl and wasallowed to warm up to RT. The reaction was extracted with ETOAc, driedover Na₂SO₄, filtered and evaporated to dryness. The crude was purifiedby column chromatography (1:1 hexane/DCM to 100% DCM) to give the titledcompound, 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one, asan offwhite solid. MS (M+1): 328.

The following compounds in Table I are additional representativeexamples of compounds of Formulas I, II, III and IV, and sub-formulasthereof, provided by the present invention. The methods used to preparethe exemplary compounds are included in Table 1, and correspond to thosedescribed in the Examples 1-7 herein above. The methods used to preparethe exemplary compounds 11-28 shown in Table 1 are as described in theExample No. (“Eg”) so indicated and herein above. Table I furtherprovides the mass and biological data (average nM IC₅₀'s for the enzymeand cell assays, provided) for each compound, where available.

TABLE I BACE 1 HEK Compound Compound Observed FRET assay cell assayExample Structure Name MW Method (uM) (uM)  2

(5R/S)-7-(2-fluoro-3- pyridinyl)-3-(2-fluoro-4- pyridinyl)-6′,7′-dihydrospiro[chro- meno[2,3-c] pyridine-5,3′- [1,4]oxazepin]-5′-amine472 1 0.001 0.003 13

(5R)-7-(2-fluoro-3- pyridinyl)-3-(2-fluoro-4- pyridinyl)-6′,7′-dihydrospiro[chro- meno[2,3-c] pyridine-5,3′- [1,4]oxazepin]-5′-amine472 1 0.139 0.078 14

(5S)-7-(2-fluoro-3- pyridinyl)-3-(2-fluoro-4- pyridinyl)-6′,7′-dihydrospiro[chro- meno[2,3-c] pyridine-5,3′- [1,4]oxazepin]-5′-amine472 1 0.0005 0.001 3B

(5S)-7-bromo-3-chloro- 6′,7′-dihydrospiro[chro- meno[2,3-c]pyridine-5,3′- [1,4]oxazepin]-5′-amine 394 3.826 0.892 3A

(5R)-7-bromo-3-chloro- 6′,7′-dihydrospiro[chro- meno[2,3-c]pyridine-5,3′- [1,4]oxazepin]-5′-amine 394 9.228 6.374  4

(3R/S)-2′-(2,2- dimethylpropoxy)-4′- fluoro-7′-(2-fluoro-3-pyridinyl)-6,7- dihydrospiro[1,4- oxazepine-3,9′- xanthen]-5-amine 480 20.001 0.012 15

(3S)-2′-(2,2- dimethylpropoxy)-4′- fluoro-7′-(2-fluoro-3-pyridinyl)-6,7- dihydrospiro[1,4- oxazepine-3,9′- xanthen]-5-amine 480 20.0005 0.007 16

(3R)-2′-(2,2- dimethylpropoxy)-4′- fluoro-7′-(2-fluoro-3-pyridinyl)-6,7- dihydrospiro[1,4- oxazepine-3,9′- xanthen]-5-amine 480 20.285 0.300 17

(5R)-7-(2-fluoro-3- pyridinyl)-3-(2-fluoro-4- pyridinyl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3- c]pyridine-5,5′- [1,4]oxazepin]-3′-amine 472 10.369 0.689 18

(S)-3-(3,4- difluorophenyl)-7-(2- fluoropyridin-3-yl)-6′,7′-dihydro-2′H- spiro[chromeno[2,3- c]pyridine-5,5′-[1,4]oxazepin]-3′-amine 489 1 0.002 0.019 19

(S)-3-(3,3- difluoropyrrolidin-1-yl)- 7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H- spiro[chromeno[2,3- c]pyridine-5,5′-[1,4]oxazepin]-3′-amine 482 3 0.003 0.004

The following compounds in Table 2 are additional representativeexamples of Formulas I-IV provided by the present invention.

TABLE 2

Ex. No. R² A³ A⁴ R⁷ X Y 20 3,6-dihydro-2H-pyran-3-yl CH N2-Fluoropyridin-3-yl CH₂ —O— 21 2,2-dimethylpropanenitrile- CH N2-Fluoropyridin-3-yl CH₂ —O— oxyl 22 3-methyl-e-oxetane- CH CH2-Fluoropyridin-3-yl —O— CH₂ methoxyl 23 3-methyl-1H-pyrazolyl- CH CH2-Fluoropyridin-3-yl- —O— CH₂ 24 3,6-dihydro-2H-pyran-4-yl CH N2-Fluoropyridin-3-yl —O— CH₂ 25 2-F-pyrrolidin-1-yl CH N2-Fluoropyridin-3-yl —O— CH₂ 26 3,6-dihydro-2H-pyran-4-yl CH N2-Fluoropyridin-3-yl CH₂ —O— 27 2,3-dimethyl-3,6-dihydro- CF N2-Fluoropyridin-3-yl CH₂ —O— 2H-pyran-4-yl 28 3-methyl-3-oxetanyl- CF N2-Fluoropyridin-3-yl —O— CH₂ ethynyl 29 3,6-dihydro-2H-pyran-3-yl CF N2-Fluoropyridin-3-yl —O— CH₂ 30 2,2-dimethylpropanenitrile- CF N2-Fluoropyridin-3-yl CH₂ —O— oxyl 31 3-methyl-e-oxetane- CF N2-Fluoropyridin-3-yl CH₂ —O— methoxyl 32 3-methyl-1H-pyrazolyl- CF N2-Fluoropyridin-3-yl —O— CH₂ 33 3,6-dihydro-2H-pyran-4-yl CF N2-Fluoropyridin-3-yl —O— CH₂ 34 2-F-pyrrolidin-1-yl CF N2-Fluoropyridin-3-yl CH₂ —O— 35 3,6-dihydro-2H-pyran-4-yl CF Npyridin-3-yl CH₂ —O— 36 2,3-dimethyl-3,6-dihydro- CF N2-Fluoropyridin-3-yl —O— CH₂ 2H-pyran-4-yl 37 3-methyl-3-oxetanyl- CF N2-Fluoropyridin-3-yl —O— CH₂ ethynyl 38 3,6-dihydro-2H-pyran-3-yl CF N2-Fluoropyridin-3-yl CH₂ —O— 39 2,2-dimethylpropanenitrile- CF N2-Fluoropyridin-3-yl CH₂ —O— oxyl

The present invention also provides methods for making compounds ofFormulas I-IV, and sub-formulas therein. For example, the compounds inTable 2 and additional examples may be made by the following methods, assimilarly described in the literature references mentioned below.

In one embodiment of the invention, there is provided a method of makinga compound of Formula I, the method comprising the step of reacting acompound 20

wherein A¹, A³, A⁴, A⁵, A⁶, A⁸, R⁷, X and Y of Formula I are as definedherein and halogen is either a bromine (Br) or chlorine (Cl), with acompound having the structure

or R²—B(OH)₂, wherein R² is as defined herein, to make a compound ofFormula I.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula I-A, the method comprising the step ofreacting a compound 20

wherein A¹, A³, A⁴, A⁵, A⁸, R⁷ and R⁹ of Formula I-A are as definedherein and halogen is either a bromine (Br) or chlorine (Cl), with acompound having the structure

or R²—B(OH)₂, wherein R² is as defined herein, to make a compound ofFormula I-A.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula I-B, the method comprising the step ofreacting a compound 20

wherein A¹, A³, A⁴, R⁷, W, X, Y and Z of Formula I-B are as definedherein and halogen is either a bromine (Br) or chlorine (Cl), with acompound having the structure

R²—B(OH)₂ or wherein R² is as defined herein, to make a compound ofFormula I-B.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula II, the method comprising the step ofreacting a compound 20

wherein A³, A⁴, R¹, R⁵, R⁶, R⁷, R⁸, X and Y of Formula II are as definedherein and halogen is either a bromine (Br) or chlorine (Cl), with acompound having the structure

or R²—B(OH)₂, wherein R² is as defined herein, to make a compound ofFormula II.

As can be appreciated by the skilled artisan, the above syntheticschemes and representative examples are not intended to comprise acomprehensive list of all means by which the compounds described andclaimed in this application may be synthesized. Further methods will beevident to those of ordinary skill in the art. Additionally, the varioussynthetic steps described above may be performed in an alternatesequence or order to give the desired compounds.

For example, in these procedures, the steps may be preceded, orfollowed, by additional protection/deprotection steps as necessary.Particularly, if one or more functional groups, for example carboxy,hydroxy, amino, or mercapto groups, are or need to be protected inpreparing the compounds of the invention, because they are not intendedto take part in a specific reaction or chemical transformation, variousknown conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the inhibitorcompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) edition, John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); A. Katritzky and A.Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd) edition (2001); M.Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis,Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne, Reductionsby the Alumino- and Borohydrides in Organic Synthesis, 2^(nd) edition,Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995).

Salts, including pharmaceutically acceptable salts, of a compound of theinvention having a salt-forming group, such as the basic amine group(s)in compounds of the invention herein, may be prepared in a conventionalmanner or manner known to persons skilled in the art. For example, acidaddition salts of compounds of the invention may be obtained bytreatment with an acid or with a suitable anion exchange reagent. A saltwith two acid molecules (for example a dihalogenide) may also beconverted into a salt with one acid molecule per compound (for example amonohalogenide); this may be done by heating to a melt, or for exampleby heating as a solid under a high vacuum at elevated temperature, forexample from 50° C. to 170° C., one molecule of the acid being expelledper molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Exemplaryand suitable salts, and their preparation, are described herein in theDefinition section of the application.

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphaticethers, e.g., Et₂O and ethylene glycol dimethylether or cyclic ethers,e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene andxylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- andt-butanol; nitriles including CH₃CN; halogenated hydrocarbons, includingCH₂Cl₂, CHCl₃ and CCl₄; acid amides including DMF; sulfoxides, includingDMSO; bases, including heterocyclic nitrogen bases, e.g. pyridine;carboxylic acids, including lower alkanecarboxylic acids, e.g., AcOH;inorganic acids including HCl, HBr, HF, H₂SO₄ and the like; carboxylicacid anhydrides, including lower alkane acid anhydrides, e.g., aceticanhydride; cyclic, linear, or branched hydrocarbons, includingcyclohexane, hexane, pentane, isopentane and the like, and mixtures ofthese solvents, such as purely organic solvent combinations, orwater-containing solvent combinations e.g., aqueous solutions. Thesesolvents and solvent mixtures may also be used in “working-up” thereaction as well as in processing the reaction and/or isolating thereaction product(s), such as in chromatography.

Purification methods are known in the art and include, for example,crystallization, chromatography (liquid and gas phase, and the like),extraction, distillation, trituration, reverse phase HPLC and the like.Reactions conditions such as temperature, duration, pressure, andatmosphere (inert gas, ambient) are known in the art and may be adjustedas appropriate for the reaction.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or generated in-situ and not isolated, prior to obtaining thefinally desired compound. Structures resulting from carrying out stepsfrom a transient starting material, structures resulting from divergencefrom the described method(s) at any stage, and structures formingstarting materials under the reaction conditions are all “intermediates”included in the invention. Further, structures produced by usingstarting materials in the form of a reactive derivative or salt, orproduced by a compound obtainable by means of the process according tothe invention and structures resulting from processing the compounds ofthe invention in situ are also within the scope of the invention.

The invention also provides new starting materials and/or intermediates,as well as processes for the preparation thereof. In select embodiments,such starting materials are used and reaction conditions so selected asto obtain the desired compound(s). Starting materials of the invention,are either known, commercially available, or can be synthesized inanalogy to or according to methods that are known in the art. Manystarting materials may be prepared according to known processes and, inparticular, can be prepared using processes described in the examples.In synthesizing starting materials, functional groups may be protectedwith suitable protecting groups when necessary. Protecting groups, theirintroduction and removal are described above.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or non-racemicmixtures thereof. While shown without respect to stereochemistry inFormulas I-IV, the present invention includes such optical isomers anddiastereomers, as well as the racemic and resolved, enantiomericallypure R and S stereoisomers, as well as other mixtures of R and Sstereoisomers and pharmaceutically acceptable salts thereof.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, e.g., by formation ofdiastereoisomeric salts, by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt. All such isomeric forms of such compounds areexpressly included in the present invention.

The compounds of the invention may also be represented in multipletautomeric forms. Tautomers often exist in equilibrium with each other,and interconvert under environmental and physiological conditions. Thecompounds of the invention may also occur in cis- or trans- or E- orZ-double bond isomeric forms. The invention expressly includes alltautomeric forms of the compounds described herein.

All crystal forms of the compounds described herein are expresslyincluded in the present invention.

The present invention also includes isotopically-labeled compounds,which are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H (deuterium), ³H(tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁶O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.

Compounds of the present invention that contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically-labeled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Deuterated (²H), Tritiated (³H) and carbon-14,i.e., ¹⁴C, isotopes are particularly preferred for their ease ofpreparation and detection. Further, substitution with heavier isotopessuch as deuterium, i.e., ²H, can afford certain therapeutic advantagesresulting from greater metabolic stability, for example increased invivo half-life or reduced dosage requirements and, hence, may bepreferred in some circumstances. Isotopically labeled compounds of thisinvention can generally be prepared by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

Biological Evaluation

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Thepharmacokinetic and pharmacodynamic properties of a compound relate,directly and indirectly, to the ability of the compound to be effectivefor its intended use.

Although the pharmacological properties of the compounds of theinvention (Formulas I-IV) vary with structural change, in general,activity possessed by compounds of Formulas I-IV may be demonstratedboth in vitro as well as in vivo. The following exemplifiedpharmacological assays have been carried out with the compoundsaccording to the invention, to assess and characterize the compound'sability to modulate BACE activity and to regulate the cleavage ofamyloid beta precursor protein, thereby reducing or inhibiting theproduction of amyloid beta.

In Vitro Enzymatic BACE FRET (Fluorescence Resonance Energy Transfer)Assay

The assay buffer used in this screen is 0.05 M acetate, pH 4.2, 10% DMSOfinal, 100 uM genapol (which is a nonionic detergent, below its CriticalMicelle Concentration). The Beta Secretase enzyme (0.2 nM) ispre-incubated for one hour with inhibitors, typically in about 1 uL ofDMSO according to a serial dilution, are added thereto. This assay iseffectively started by the addition of FRET substrate (50 nM) and thecombination is incubated for one hour. The FRET assay is terminated withby addition of Tris buffer, which raises the pH to neutrality, and thefluorescence is determined. The FRET substrate is a peptide withcommercially available fluorophore and quencher, on opposite sides ofthe BACE cleavage site. Proteolytic cleavage of the FRET substratereleases quenching of fluorescence (excitation 488 nm and emission 425nm). Where available, the in-vitro BACE FRET enzyme data for each of theExamples is provided in Table I.

In Vitro BACE Cell-Based Assay

The cell-based assay measures inhibition or reduction of Aβ40 inconditioned medium of test compound treated cells expressing amyloidprecursor protein.

Cells stably expressing Amyloid Precursor Protein (APP) were plated at adensity of 40K cells/well in 96 well plates (Costar). The cells werecultivated for 24 hours at 37° C. and 5% CO₂ in DMEM supplemented with10% FBS. The test compounds were then added to cells in 10-point doseresponse concentrations with the starting concentration being either 100μM or 10 μM. The compounds were diluted from stock solutions in DMSO andthe final DMSO concentration of the test compounds on cells was 0.1%.After 24 h of incubation with the test compounds the supernatantconditioned media was collected and the Aβ40 levels were determinedusing a sandwich ELISA. The IC₅₀ of the compound was calculated from thepercent of control or percent inhibition of Aβ40 as a function of theconcentration of the test compound.

The sandwich ELISA to detect Aβ40 was performed in 96 well microtiterplates, which were pre-treated with goat anti-rabbit IgG (Pierce). Thecapture and detecting antibody pair that were used to detect Aβ40 fromcell supernatants were affinity purified pAb40 (Biosource) andbiotinylated 6E10 (Signet Labs Inc.), respectively. The optimalconcentration for the pAb40 antibody was 3 μg/ml in Superblock/TBS(Pierce) that was supplemented with 0.05% Tween 20 (Sigma). Optimalconcentration for the detection antibody 6E10-biotinylated was 0.5 μg/mlin Superblock/TBS (Pierce) that had been supplemented with 2% normalgoat serum and 2% normal mouse serum.

Cellular supernatants were incubated with the capture antibody for 3 hat 4° C., followed by 3 wash steps in TBS-tween (0.05%). The detectingantibody incubation was for 2 h at 4° C., again followed by the washsteps as described previously. The final readout of the ELISA isTime-Resolved Fluorescence (counts per minute) using Delfia reagentsStreptavidin-Europium and Enhancement solutions (Perkin Elmer) and theVictor 2 multilabel counter (Perkin Elmer). Where available, thein-vitro BACE cell based data for each of the Examples is provided inTable I.

In Vivo Inhibition of Beta-Secretase

Several animal models, including mouse, rat, dog, and monkey, may beused to screen for inhibition of beta-secretase activity in vivofollowing administration of a test compound sample. Animals used in thisinvention can be wild type, transgenic, or gene knockout animals. Forexample, the Tg2576 mouse model, prepared and conducted as described inHsiao et al., 1996, Science 274, 99-102, and other non-transgenic orgene knockout animals are useful to analyze in vivo inhibition ofAmyloid beta peptide (Abeta) production in the presence of inhibitorytest compounds. Generally, 2 to 18 month old Tg2576 mice, gene knockoutmice or non-transgenic animals are administered test compoundsformulated in vehicles, such as cyclodextran, phosphate buffers,hydroxypropyl methylcellulose or other suitable vehicles. One totwenty-four hours following the administration of compound, animals aresacrificed, and brains as well as cerebrospinal fluid (CSF) and plasmaare removed for analysis of A-beta levels and drug or test compoundconcentrations (Dovey et al., 2001, Journal of Neurochemistry, 76,173-181) Beginning at time 0, animals are administered by oral gavage,or other means of delivery such as intravenous injection, an inhibitorytest compound of up to 100 mg/kg in a standard, conventionalformulation, such as 2% hydroxypropyl methylcellulose, 1% Tween80. Aseparate group of animals receive 2% hydroxypropyl methylcellulose, 1%Tween80 alone, containing no test compound, and serve as avehicle-control group. At the end of the test period, animals aresacrificed and brain tissues, plasma or cerebrospinal fluid arecollected. Brains are either homogenized in 10 volumes (w/v) of 0.2%diethylamine (DEA) in 50 mM NaCl (Best et al., 2005, Journal ofPharmacology and Experimental Therapeutics, 313, 902-908), or in 10volumes of 0.5% TritonX-100 in Tris-buffered saline (pH at about 7.6).Homogenates are centrifuged at 355,000 g, 4° C. for 30 minutes. CSF orbrain supernatants are then analyzed for the presence of A-beta peptideby specific sandwich ELISA assays based on ECL(Electrochemiluminescence) technology. For example, rat Abeta40 ismeasured using biotinylated-4G8 (Signet) as a capture antibody and Fab40(an in-house antibody specific to the C-terminal of Abeta40) as adetection antibody. For example, 4 hours after administration of 30mg/kg oral dose of the test compound in 2% hydroxypropylmethylcellulose, 1% Tween80 (pH2.2) to 200 g male Sprague Dawley rats,amyloid beta peptide levels are measured for reduction by X % and Y % incerebrospinal fluid and brain, respectively, when compared to the levelsmeasured in the vehicle-treated or control mice. Actual vehicles used:Oral: 2% HPMC, 1% Tween80, pH 2.2

-   -   IV: 5% EtOH, 45% Propylene glycol in 5% Dextrose

The compounds of the invention may be shown to reduce the formationand/or deposition of amyloid beta peptide in the cerebrospinal fluid(CSF) as well as in the brain of a mouse or rat at both 10 mpk (mpk=mgcompound per kg animal) and 30 mpk dosing concentrations after 4 hrs.

Indications

De Meyer et al re-affirm the believed role which the accumulation ofbeta-amyloid protein (A-beta) in cerebral spinal fluid (CSF) in asubject plays in the progression of symptoms, initially revealed as mildcognitive impairment, which ultimately leads to AD. Arch Neural.67(8):949-956, 2010. Amyloid-b (Ab) peptides generated from amyloidprecursor protein (APP) by proteolytic cleavage, such as by aspartylprotease enzymes including beta-secreatase (BACE) and gamma-secretase,likely play a causal role in AD pathogenesis (Tanzi and Bertram, Cell,(120): 545-555, 2005; Walsh and Selkoe, Neuron, (44): 181-193, 2004).Although the precise mechanisms of Ab toxicity are unclear, oligomericforms of Ab may contribute to cognitive decline by altering synapticstructure and function (Palop and Mucke, Nat. Neuroscience, (13):812-818, 2010; Selkoe, Behavioral Brain Res., (192): 106-113, 2008;Shankar et al., Nat. Medicine (14): 837-842, 2008). Transgenic mousemodels that overexpress mutant APP and produce high levels of Ab showamyloid plaque deposition, synaptic deficits, learning and memoryimpairments, and other behavioral abnormalities (Games et al., Nature,(373): 523-527, 1995; Go{umlaut over ( )}tz et al., Molecular Psychiatry(9): 664-683, 2004; Hsia et al., Proc. Natl. Academy of Science USA(96): 3228-3233, 1999; Hsiao et al., Science (274): 99-102, 1996, citingHarris et al, Neuron (68): 428-441, 2010).

The compounds of the invention have been shown to modulate, andspecifically inhibit the activity of the beta-secretase enzyme, therebyreducing the A-beta peptide fragments believed to be responsible forAlzheimer's Disease (AD). Bapineuzamab, a monoclonal amino-terminusspecific anti-amyloid antibody is presently in Phase III clinical trialsfor the treatment of AD. Alzheimer's Research & Therapy, 1:2, 2009. Eachof the known genetic causes of AD is linked to A-beta. Dementia, Down'sSyndrome to APP over-production, are all believed to be linked to thedeposition of A-beta on the brain. With methods for identifying brainamyloid deposition, positron emission scanning (PET) and CSFmeasurements of Ab42, identification of AD suffering individuals needingtreatment is becoming easier amd more common. It is firmly believed thatby reducing the formation of A-beta, one can begin to pre-treat AD.Vassar et al, Journal of Neuroscience, 29 (41):12787-12794, 2009. Onepublished pathway for treatment of AD is inhibition of beta-secretase.Tirrell, Bloomberg News, The Boston Globe, Jan. 7, 2010.

The US biotech company CoMentis is developing an orally bioavailablesmall molecule CTS-21166, a highly potent, highly selective andefficacious brain-penetrating beta-secretase inhibitor. CoMentissuccessfully completed a Phase I study of CTS-21166 in healthyvolunteers in 2008. Results indicated that CTS-21166 was safe,well-tolerated and pharmacodynamically active at all dose levels. Allclinical subjects administered CTS-21166 showed area-under-curve (AUC)reduction in plasma A-Beta40 reductions ranging from 40-75%. Because ofthe urgent need for AD treatment, Phase II studies for CTS-2166 areplanned, or ongoing, for AD patients. In preclinical studies, CTS-21166exhibits excellent efficacy, selectivity, brain penetration andpharmacologic activity.

Accordingly, compounds of the invention, i.e., compounds of Formulas I,II, III and IV, are useful for, but not limited to, the prevention ortreatment of beta-secretase related diseases, including Alzheimer'sdisease. The compounds of the invention have the ability to modulate theactivity of beta secretase enzyme, thereby regulating the production ofamyloid beta (Abeta peptide) and reducing the formation and depositionof Abeta peptide in both the cerebral spinal fluid as well as in thebrain, resulting in a decrease of amyloid plaque on the brain. In oneembodiment of the invention, there is provided a method of treating adisorder related to a beta-secretase enzyme in a subject, the methodcomprising administering to the subject an effective dosage amount of acompound of Formulas I, II, III, IV, and sub-formulae thereof. Inanother embodiment, there is provided a method of reducing production ofamyloid beta, and of reducing plaque formation on the brain. In anotherembodiment, there is provided a method for the treatment, prevention oramelioration of a disease or disorder characterized by the elevatedbeta-amyloid deposits or beta-amyloid levels in a subject, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound according to any of Formulas I-IV. In yet anotherembodiment, the invention provides a method of treating Alzheimer'sdisease, cognitive impairment including mild, moderate and/or severe,Down's Syndrome, cognitive decline, senile dementia, cerebral amyloidangiopathy or a neurodegenerative disorder.

Accordingly, the compounds of the invention would be useful in therapyas CNS agents in treating neurological disorders and related conditionsin subjects.

Besides being useful for human treatment, the compounds of the inventionmay be useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Forexample, animals including horses, dogs, and cats may be treated withcompounds provided herein.

Formulations and Method of Use

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) which may be in need of preventative treatment, such as, forexample, for pain, inflammation and the like. Treatment also encompassesprophylactic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman). Generally, the subject is initially diagnosed by a licensedphysician and/or authorized medical practitioner, and a regimen forprophylactic and/or therapeutic treatment via administration of thecompound(s) or compositions of the invention is suggested, recommendedor prescribed.

The amount of compound(s) which is/are administered and the dosageregimen for treating neurological disorders and beta-secretase mediateddiseases with the compounds and/or compositions of this inventiondepends on a variety of factors, including the age, weight, sex andmedical condition of the subject, the type of disease, the severity ofthe disease, the route and frequency of administration, and theparticular compound employed. Thus, the dosage regimen may vary widely,but can be determined routinely using standard methods. A daily dose ofabout 0.01 to 500 mg/kg, advantageously between about 0.01 and about 50mg/kg, more advantageously about 0.01 and about 30 mg/kg, and even moreadvantageously between about 0.1 and about 10 mg/kg body weight may beappropriate, and should be useful for all methods of use disclosedherein. The daily dose can be administered in one to four doses per day.

While it may be possible to administer a compound of the inventionalone, in the methods described, the compound administered normally willbe present as an active ingredient in a pharmaceutical composition.Thus, in another embodiment of the invention, there is provided apharmaceutical composition comprising a compound of this invention incombination with a pharmaceutically acceptable excipient, which includesdiluents, carriers, adjuvants and the like (collectively referred toherein as “excipient” materials) as described herein, and, if desired,other active ingredients. A pharmaceutical composition of the inventionmay comprise an “effective amount” of a compound of the invention or an“effective dosage amount” of a compound of the invention. An “effectivedosage amount” of a compound of the invention includes an amount lessthan, equal to or greater than an effective amount of the compound. Forexample, a pharmaceutical composition in which two or more unit dosages,such as in tablets, capsules and the like, are required to administer aneffective amount of the compound, or alternatively, a multi-dosepharmaceutical composition, such as powders, liquids and the like, inwhich an effective amount of the compound is administered byadministering a portion of the composition.

The compound(s) of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The compounds and compositions of the present invention may,for example, be administered orally, mucosally, topically, rectally,pulmonarily such as by inhalation spray, or parentally includingintravascularly, intravenously, intraperitoneally, subcutaneously,intramuscularly intrasternally and infusion techniques, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,advantageously from about 1 to 500 mg, and typically from about 5 to 150mg. A suitable daily dose for a human or other mammal may vary widelydepending on the condition of the patient and other factors, but, onceagain, can be determined using routine methods and practices.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants or other “excipients”appropriate to the indicated route of administration. If orallyadministered on a per dose basis, the compounds may be admixed withlactose, sucrose, starch powder, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, to form the final formulation. For example,the active compound(s) and excipient(s) may be tableted or encapsulatedby known and accepted methods for convenient administration. Examples ofsuitable formulations include, without limitation, pills, tablets, softand hard-shell gel capsules, troches, orally-dissolvable forms anddelayed or controlled-release formulations thereof. Particularly,capsule or tablet formulations may contain one or morecontrolled-release agents, such as hydroxypropylmethyl cellulose, as adispersion with the active compound(s).

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, and preferably from about 0.1 to about 10mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.Accordingly, in yet another embodiment of the present invention, thereis provided a method of manufacturing a medicament, the methodcomprising combining an amount of a compound according to Formulas I-IVwith a pharmaceutically acceptable carrier to manufacture themedicament.

In yet another embodiment, the invention provides a method ofmanufacturing a medicament for the treatment of Alzheimer's disease, themethod comprising combining an amount of a compound according toFormulas I-IV with a pharmaceutically acceptable carrier to manufacturethe medicament.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of beta-secretase,gamma-secretase and/or other reagents known in influence the formationand/or deposition of amyloid beta, otherwise responsible for theformation of plaque on the brain.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I, II and III may also be administered sequentially withother known medicinal agents. The invention is not limited in thesequence of administration; compounds of the invention may beadministered either prior to, simultaneous with or after administrationof the known anti-inflammatory agent.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula I

or a stereoisomer, tautomer, hydrate, solvate or pharmaceuticallyacceptable salt thereof, wherein A¹ is CR¹ or N; A³ is CR³ or N; A⁴ isCR⁴ or N; A⁵ is CR⁵ or N; A⁶ is CR⁶ or N; A⁸ is CR⁸ or N, provided thatno more than one of A¹, A³, A⁴, A⁵, A⁶ and A⁸ is N; each of R¹, R⁴, R⁵and R⁸, independently, is H, F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH,—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl,wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionallysubstituted with 1-3 substituents of F, oxo or OH; R² is Cl, Br,C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or —Si(CH₃)₃,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹; eachof R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl; R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NHC(═O)R⁹,—C(═O)NHR⁹, —NHS(O)₂R⁹, —S(O)₂NHR⁹, —NH-phenyl, —NH-benzyl, phenyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹; eachR⁹, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, morpholinyl, pyrazolyl, isoxazolyl,dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,oxetanyl or dioxolyl, wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkylamino-, C₁₋₆dialkylamino-,C₁₋₆alkoxyl, C₁₋₆thioalkoxyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, morpholinyl, pyrazolyl,isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, isoptionally substituted independently with 1-5 substituents of F, Cl, CN,NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,C₁₋₃alkylamino-, C₁₋₃dialkylamino, C₁₋₃thioalkoxyl, or oxetanyl; and—X—Y— is —CR¹⁰R¹⁰—O—, —O—CR¹⁰R¹⁰—, —CR¹⁰R¹⁰—S— or —S—CR¹⁰R¹⁰, whereineach R¹⁰, independently, is H or F.
 2. The compound of claim 1, or astereoisomer or pharmaceutically acceptable salt thereof, wherein eachof R¹, R⁴, R⁵ and R⁸, independently, is H, F, Cl, CF₃, OCF₃, methyl,ethyl, CN, OH, OCH₃, SCH₃, NHCH₃ or C(O)CH₃; one of R² and R⁷,independently, is C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, phenyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or —Si(CH₃)₃,wherein the C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-3 substituents of R⁹; theother of R² and R⁷, independently, is phenyl, pyridyl, pyrimidyl,pyrazinyl or pyridazinyl, wherein the phenyl, pyridyl, pyrimidyl,pyrazinyl and pyridazinyl are optionally substituted, independently,with 1-3 substituents of R⁹; and each of R³ and R⁶, independently, is H,halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl,SC₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl.
 3. The compound of claim 1,or a stereoisomer or pharmaceutically acceptable salt thereof, whereinR² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, or a ring selectedfrom phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionallysubstituted, independently, with 1-3 substituents of R⁹; each of R¹, R⁴,R⁵ and R⁸, independently, is H, F, methyl, CN or OH; each of R³ and R⁶,independently, is H, F, Cl, CF₃, methyl, CN, OH, OCH₃, SCH₃ or NHCH₃; R⁷is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thienyl, said ring optionally substituted,independently, with 1-3 substituents of R⁹; and —X—Y— is CH₂—O—,—O—CH₂—, —CH₂—S— or —S—CH₂—.
 4. A compound of claim 1 having a FormulaII:

or a stereoisomer, tautomer, hydrate, solvate or pharmaceuticallyacceptable salt thereof, wherein A³ is CR³ or N; A⁴ is CR⁴ or N,provided that no more than one of A³ and A⁴ is N; each of R¹, R⁴, R⁵ andR⁸, independently, is H, F, Cl, Br, CF₃, OCF₃, C₁₋₆-alkyl, CN, OH,—OC₁₋₆-alkyl, —S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl or —C(O)C₁₋₆-alkyl,wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of —OC₁₋₆-alkyl,—S(O)_(o)C₁₋₆-alkyl, —NHC₁₋₆-alkyl and —C(O)C₁₋₆-alkyl are optionallysubstituted with 1-3 substituents of F, oxo or OH; R² is Cl, Br,C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl, cyclohexyl or —Si(CH₃)₃,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NH-phenyl, —NH-benzyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹; eachof R³ and R⁶, independently, is H, halo, haloalkyl, haloalkoxyl,C₁₋₆-alkyl, CN, OH, OC₁₋₆-alkyl, S(O)_(o)C₁₋₆-alkyl, NHC₁₋₆-alkyl orC(O)C₁₋₆-alkyl; R⁷ is C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NHC₁₋₆alkyl, —N(C₁₋₃alkyl)₂, —NHC(═O)R⁹,—C(═O)NHR⁹, —NHS(O)₂R⁹, —S(O)₂NHR⁹, —NH-phenyl, —NH-benzyl, phenyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl or cyclohexyl, wherein theC₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NHC₁₋₆alkyl, —N(C₁₋₃ alkyl)₂, —NH-phenyl, —NH-benzyl, phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclopentyl and cyclohexyl areoptionally substituted, independently, with 1-5 substituents of R⁹; eachR⁹, independently, is halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,—C(O)NHCH₃, oxo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl,C₁₋₆alkylamino-, C₁₋₆dialkylamino-, C₁₋₆alkoxyl, C₁₋₆thioalkoxyl,phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, morpholinyl, pyrazolyl, isoxazolyl,dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,oxetanyl or dioxolyl, wherein each of the C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₁₋₆alkylamino-, C₁₋₆dialkylamino-,C₁₋₆alkoxyl, C₁₋₆thioalkoxyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, morpholinyl, pyrazolyl,isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, isoptionally substituted independently with 1-5 substituents of F, Cl, CN,NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,C₁₋₃alkylamino-, C₁₋₃dialkylamino, C₁₋₃thioalkoxyl, or oxetanyl; and—X—Y— is, —CR¹⁰R¹⁰—O—, —O—CR¹⁰R¹⁰—, —CR¹⁰R¹⁰—S— or —S—CR¹⁰R¹⁰, whereineach R¹⁰, independently, is H or F.
 5. The compound of claim 1, or astereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein R¹ is H or F; A³ is CH, CF or N; A⁴ is CH, CF or N; R⁵ is H orF; R⁶ is CH, CF or N; R⁸ is H or F; and —X—Y— is —CH₂—O— or —O—CH₂—. 6.The compound of claim 1, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein each of R¹, R⁴, R⁵ and R⁸,independently, is H, F, Cl, CF₃, OCF₃, methyl, ethyl, CN, OH, OCH₃,SCH₃, NHCH₃ or C(O)CH₃; one of R² and R⁷, independently, is C₂₋₄alkynyl,—OC₁₋₆alkyl, —SC₁₋₆alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl,pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl,morpholinyl, azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl, cyclohexyl or —Si(CH₃)₃, wherein the C₂₋₄alkynyl,—OC₁₋₆alkyl, —SC₁₋₆alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl,pyrrolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclopentyl and cyclohexyl are optionally substituted, independently,with 1-3 substituents of R⁹; the other of R² and R⁷, independently, isphenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl, wherein thephenyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl are optionallysubstituted, independently, with 1-3 substituents of R⁹; each of R³ andR⁶, independently, is H, halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, CN,OH, OC₁₋₆-alkyl, SC₁₋₆-alkyl, NHC₁₋₆-alkyl or C(O)C₁₋₆-alkyl; and —X—Y—is —CH₂—O— or —O—CH₂—.
 7. The compound of claim 1, or a stereoisomer orpharmaceutically acceptable salt thereof, wherein R⁷ is a ring selectedfrom phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl,furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, pyrrolidinyl,tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, said ringoptionally substituted, independently, with 1-3 substituents of R⁹. 8.The compound of claim 1, or a stereoisomer or pharmaceuticallyacceptable salt thereof, wherein R² is Cl, Br, C₁₋₆-alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, or a ring selected from phenyl, pyridyl, pyrimidyl,pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl,dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionallysubstituted, independently, with 1-3 substituents of R⁹; each of R¹, R⁴,R⁵ and R⁸, independently, is H, F, methyl, CN or OH; each of R³ and R⁶,independently, is H, F, Cl, CF₃, methyl, CN, OH, OCH₃, SCH₃ or NHCH₃; R⁷is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl or thienyl, said ring optionally substituted,independently, with 1-3 substituents of R⁹; and —X—Y— is —CH₂—O— or—O—CH₂—.
 9. The compound of claim 1, or a stereoisomer orpharmaceutically acceptable salt thereof, wherein A³ is N; A⁴ is CR⁴; R²is halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,or a ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl,tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,pyrrolidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,cyclobutyl, cyclopentyl or cyclohexyl, wherein the C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionally substituted,independently, with 1-3 substituents of R¹⁰; each of R¹, R⁴, R⁵ and R⁸,independently, is H, F, methyl, CN or OH; R⁶ is H, F, Cl, CF₃, methyl,CN, OH, OCH₃, SCH₃ or NHCH₃; R⁷ is a ring selected from phenyl, pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, triazinyl or thiophenyl, said ringoptionally substituted, independently, with 1-3 substituents of R⁹; and—X—Y— is —CH₂—O— or —O—CH₂—.
 10. The compound of claim 4, or astereoisomer or pharmaceutically acceptable salt thereof, wherein A³ isCR³; A⁴ is CR⁴ or N; R² is halo, haloalkyl, haloalkoxyl, C₁₋₆-alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, or a ring selected from phenyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl,pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,tetrahydrofuranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,piperidinyl, piperazinyl, morpholinyl, azetidinyl,8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,2-oxo-7-aza-[3,5]-spironon-7-yl, cyclobutyl, cyclopentyl or cyclohexyl,wherein the C₁₋₆-alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl and ring are optionallysubstituted, independently, with 1-3 substituents of R¹⁰; each of R¹,R⁴, R⁵ and R⁸, independently, is H, F, methyl, CN or OH; each of R³ andR⁶, independently, is H, F, Cl, CF₃, methyl, CN, OH, OCH₃, SCH₃ orNHCH₃; R⁷ is a ring selected from phenyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, triazinyl or thiophenyl, said ring optionallysubstituted, independently, with 1-3 substituents of R⁹; and —X—Y— is—CH₂—O— or —O—CH₂—.
 11. The compound of claim 1, or a stereoisomer orpharmaceutically acceptable salt thereof, selected from(5R/S)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)-6′,7′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine;(5R)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)-6′,7′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine;(5S)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)-6′,7′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine;(5S)-7-bromo-3-chloro-6′,7′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine;(5R)-7-bromo-3-chloro-6′,7′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine;(3R/S)-2′-(2,2-dimethylpropoxy)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-6,7-dihydrospiro[1,4-oxazepine-3,9′-xanthen]-5-amine;(3S)-2′-(2,2-dimethylpropoxy)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-6,7-dihydrospiro[1,4-oxazepine-3,9′-xanthen]-5-amine;(3R)-2′-(2,2-dimethylpropoxy)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-6,7-dihydrospiro[1,4-oxazepine-3,9′-xanthen]-5-amine;and(5R)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,5′-[1,4]oxazepin]-3′-amine.12. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable excipient.
 13. A method ofreducing the levels of beta amyloid peptide in the cerebral spinal fluidof a subject, the method comprising administering to the subject aneffective dosage amount of a compound according to claim
 1. 14. A methodof treating Alzheimer's disease, cognitive impairment or a combinationthereof in a subject, the method comprising administering to the subjectan effective dosage amount of a compound to claim
 1. 15. A method ofclaim treating a neurological disorder selected from the groupconsisting of mild cognitive impairment, Down's syndrome, Hereditarycerebral hemorrhage with dutch-type amyloidosis, cerebral amyloidangiopathy, degenerative dementia, dementia associated with Parkinson'sdisease, dementia associated with supranuclear palsy, dementiaassociated with cortical basal degeneration, diffuse lewy body type ofAlzheimer's disease or a combination thereof in a subject, the methodcomprising administering to the subject an effective dosage amount of acompound according to claim
 1. 16. A method of reducing the formation ofplaque on the brain of a subject, the method comprising administering tothe subject an effective dosage amount of a compound according toclaim
 1. 17. A process for preparing a compound of claim 1, the processcomprising the step of reacting a compound 20

wherein A¹, A³, A⁴, A⁵, A⁶, A⁸, R⁷, X and Y of compound 20 are asdefined in claim 1 and leaving group (LG) is Cl or Br, with a compoundhaving the structure

or R⁷—B(OH)₂, wherein R² is as defined in claim 1 to prepare thecompound of claim 1.